Cyber knife in urological malignancies

Radiosurgery in urological malignancies

Debnarayan Dutta, MDConsultant Radiation Oncologist

Apollo Speciality Hospital, Chennai

INDIA

[email protected]

Apollo Speciality Hospital, Chennai

Cancer management Facilities- Medical, surgical & radiation oncology unit

- 320 slice CT scan

- MRI scan with ‘time of flight’ technology

- Bone marrow transplant unit

- Two LA with 3DCRT, IMRT & IGRT

- HDR brachytherapy

- BrainLAB system

- CyberKnife

- Tumour board

- Multi-disiplinary support system

- 17 yrs experience in radiation therapy

- 8 yrs experience in IMRT

- 10 yrs experience in BrainLAB

‘The Week’ magazine ranking 2010

3rd rank in oncology

(after TMH & AIIMS)

Cyberknife

Accuray Confidential

Linear

Accelerator

Manipulator

Image

Detectors

X-ray Sources

IMAGING

SYSTEM

ROBOTIC

DELIVERY

SYSTEM

TARGETING SOFTWARE

Robotic Radiosurgery

Highly precise RT delivery system

- Respiratory tracking

- Fiducial based tracking system

- Intra-fraction motion correction

- Uncomparable dose distribution

- X-ray based image verification

Hypofractionated RT

- High dose short course RT

- Higher BED delivered to target

Ideal for moving targets

Unique features of Cyberknife:

‘Frameless’ treatment of intra & extra cranial disease

Both intra & extra-ceanial

tumours can be treated


– Relies on intra-fraction imaging to continually assess target movement

– Stated total clinical accuracy of .50mm

Chang et al.Neurosurgery, 2003

Murphy MJ et al. Int J Radiat Oncol Biol Phys. 2003

Sub-millimeter accuracy

CyberKnifeNovalis / Trilogy


Unmatched dose distribution

Higher low dose spillage with Novalis.

Better dose conformity with Cyberknife

DRR

LIVE


‘6-D tracking system’


‘Fiducial tracking’

Fiducial tracking is the most effective method of tumour tracking


Non-coplanar field arrangement


‘Dose painting’ technique

– Highly conformal dose delivery

– Both isocentrically and non-isocentrically

– Non-coplanar beam arrangement

– Flexible fractionation schedule

– Flexible treatment delivery

Synchrony respiratory tracking system: Cyberknife

Synchrony respiratory tracking system• Continuously tracks tumor motion during treatment

– Synchrony RespiratoryTracking System

• Continual tracking of motion throughout treatment

• Continuously adapts to variations in breathing patterns in 3D

– Model updated throughout treatment based on both internal & external motion

• Beam automatically corrects for target movement

0.75mm targeting accuracy


Shorter overall treatment time

Site Schedule Days

Lung cancer 60 Gy/3# 3 days

45 Gy/3# 3 days

Prostate 36.25 Gy/5# 5 days

Brain tumours 20-30 Gy/3-5 # 3-5 days

AVMs 12-25 Gy/1# 1 day

Single fraction Rx 12-25 Gy/1# 1 day

Cyberknife IMRT

36.25 Gy/5# 70 Gy/35#

~3 hours ~10 hours

Daily treatment

Cyberknife: 45 min

IMRT: 15 min

With Cyberknife both total duration (min) &

treatment days are short

Total treatment duration in hrs

• Highest level of comfort

• Pain-free / No anesthesia

• No invasive head or body frame

• No breath-holding during treatment

• Significantly reduces treatment time

• Treats only affected areas

• Minimizes acute side effects

• Treats tumors anywhere in the body

• Sub-millimeter accuracy

• Dynamic (Inter-fraction) motion tracking

Cyberknife : Advantages

Radiosurgery in urological malignancies

- Prostate cancer

- Renal cell cancer

- Urinary bladder cancer

• Most prevalent malignancy in males in western community

• 2nd MC cause of mortality in the west

• Uncommon in Asians, probably shorter lifespan

• In TMH, constitutes 2.4% of all registered pts in 2000

• In recent years, more early prostate cancer patients are diagnosed

with prostate cancer

• Prostate cancer is slow growing tumour, risk of bone metastasis is

high in ‘high risk’ group patient

Prostate cancer

Risk stratification

RISK STRATIFICATION

LOW RISK INTERMEDIATE HIGH

T1,2a, PSA < 10 ng/ml,

GS</=6

T2b,

GS=7

T3,4,PSA>20ng/ml,

GS>7

Wait & watch

Surgery

Radiation therapy

HT

Radiosurgery

Combination

Surgery

Radiation therapy

HT

Radiosurgery

Combination

Surgery

Radiation therapy

HT

Radiosurgery

Combination

Radiotherapy

Radiation techniques:

2D Planning

Conformal Radiation therapy

- 3D-CRT

- IMRT

- SBRT

Target volume:

CTV – prostate with capsule + SV

T1 & small T2 with less PSA less GS only prostate is sufficient.

PTV – 1 cm margin.

Inclusion of pelvic lymph nodes still controversial.

Ca prostate Incidence of pelvic LN metastasis at diagnosis

Study T1a,b T1c T2a T2b,c T3

Pisansky 12/457

(2.6%)

15/456

(3.3%)

130/1206

(10.8%)

81/320

(25%)

-

Petros &

Catalona

2/61

(3.3%)

33/425

(7.8%)

0

Sands 6/127 (5%) 41/243

(16.9%)

95/199

(47.7%)

Van

Poppel

2/40(5%) 18/199

(9%)

25/46

(54%)

Hanks 1/21(5%) 38/135(28%) 48/95(50%)

Radiotherapy Radiation therapy schedules

Conventional fractionation:

- 70Gy/ 35# / 7 wk

- 2Gy/#

- Acute rectal & bladder toxicity

Hypofractionation schedule:

- High dose per fraction, short course treatment

- Equivalent loco-regional control

Ultra-hypofractionation schedule:

- Very short course, high dose per fraction

- Usual treatment duration 5 to 7 days

Conformal Radiation therapy

reduces toxicity

• RCT

• Royal Marsden Tait et al.Gr 2 or more 5 Vs 15%.

• Rotterdam trial Koper et al.

Grade 2 GI toxicity (32% vs. 19%, p = 0.02).

• M.D. Anderson Storey et al.

No dif but Dose 78 vs 70.

• Nonrandomized trials

• 15/27 improvement

• Most pronounced when dose escalation was not used.

• When dose escalation was used, no increased toxicity was demonstrated, except when the dose to the rectum >75 Gy.

• No article suggested increased toxicity with 3D-CRT for similar doses delivered compared with

conventional RT.

WPRT VS PORT:RTOG trial 9413

1323 patients with localized disease andrisk of LN involvement >15% & PSA <100

WP RT+ NCHT

PFS 60%

PO RT+ NCHT

44%

WP RT+ AHT

49%

PO RT+ AHT

50%

• WP RT NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and

compared with WPRT + AHT in patients with a risk of LN involvement of 15%.

•Median follow-up : 59.5 mnths

• No OS advantage JCO 2003

Subset analysis of RTOG 9413

Subset of 694 patients studied

325 patients WP RT N&CHT

Median PFS 5.2yrs

324 patients PO RT N&CHT.

FS ≥10 × 11 but <11 × 11

cm)

MP FS<10x11cm

•Median PFS was 5.2, 3.7, and 2.9 years ( p 0.02).

•7-year PFS was 40%, 35%, and 27%

•RT field size has a major impact on PFS, and it is advised that

nodal treatment should be done in patients with a risk of LN inv >15% .

Roach IJROBP 2006

Dose escalation: improve LC

Author Study type Patient criteria Study details Results

Kurban et al Prospective

multi-

institutional

N= 4839

1986-95

T1-2 low risk

prostate cancer

No neo-adj HT

RT dose 60-78 Gy

3DCRT planming

Median FU 6.3 yrs

8-year PSA control rates were 72

to 93%. Dose >72 Gy had lower

PSA relapse rate.

Zietman MDACC

Randomized

N= 393

T1-2 disease

PSA < 105ng/dl

Arm 1: Conv RT 70.2 Gy

Arm 2: Conv RT 79.2 Gy

Median FU: 5.5 yrs

5-yr PSA rFS higher with dose

escalation (61% vs 80%). 49%

risk reduction in biochemical

failure.

Pollack et al MDACC

Randomized

N=301

Low risk prostate

cancer

Arm 1 (n=150): Conv RT 70

Gy

Arm 2 (151): 3DCRT 78 Gy

PSA rFS higher with dose

escalation (70% versus 64%;

p=0.03)

Peeters et al Randomized

Netherland

N=669

T1-4

Arm 1 (n=150): Conv RT 68

Gy

Arm 2 (151): Conv RT 78 Gy

Median FU: 51 months

5-yr PSA relapse-free survival

superior with high dose (64% vs.

54%; p = .02).

Zelefsky et al Randomized

MSKCC

N=1100

1988-98

RT dose systematically

increased from 64.8 to 86.4

Gy by increments of 5.4 Gy

in consecutive groups of pts.

5-yr PSA rFS was higher with

dose escalation in favorable,

intermediate and unfavourable

groups.

Zelefsky et al Single arm N=561

1996-2000

RT dose: 81 Gy to PTV 8-yr PSA rFS for favorable-,

intermediate-, and unfavorable-

risk groups were 85%, 76%, 72%

Prostate Cancer: Dose escalation studies

Intensity modulated radiation therapy

76- 81 Gy at 2 Gy/# dose delivered

Dose to target higher

Rectal & Bladder dose is high

High acute reactions

Dose escalation methods

IMRT/ 3DCRT


Brachytherapy


Brachytherapy seed implant


HDR Brachytherapy implant

HDR brachytherapy implant

High dose rate

Invasive procedure

Skill dependent

Toxicities after Radiation therapy

Rectal toxicity

- Telengectasia

- Bleeding

- Bladder toxicity

- Incontinence

- Bleeding

- Thimble bladder

- Urethral stricture

-Erectile dysfunction

- Quality of life

Toxicity depends upon dose

Motion during treatment is a problem in Prostate Cancer

Cyberknife is the only technology which corrects movement between each field treatment

Author Study Patient criteria Study details Results

Martin Prospect

ive

PMH

N= 92

June 2001- Mar

2004

60 Gy /20 fr/ 4 wks

IMRT, FU: 38 mo

3 yr PSA relapse free was 76%.

RTOG Gr ≥3 GI toxicity in 1 patient

Kupelian Clevelan

d Clinic

N= 770

1998-2005

70 Gy; 2.5-Gy/fr/ 5

wks.

FU: 45 mo

5 yr PSA relapse free of low,

intermediate and high-risk disease was

95%, 85%, and 68%, respectively.

Livsey Retrosp

ective

Manche

ster

N= 705 men

T1-T4 disease

1995 -1998

Conformal RT (50

Gy/16fr/ 22 days)

Median FU: 48

months

Favourable, intermediate, poor

prognostic groups biochemical control

was 82%, 56%, and 39%. RTOG Gr ≥2

GI and bowel toxicity was 5% and 9%.

Lukka Randomi

zed

NCI

Canada

N= 936

Mar 1995-

Dec1998

Long arm: 66 Gy/33

fr 45 days

Short arm: 52.5

Gy/20 fr 28 days

5 yrs, PSA relapse free survival was

52.95% in long and 59.95% in short arm.

GI toxicity higher with short arm (11% vs

7%)

Tsuji Chiba

Japan

N=201

June 1995-Feb

2004

Three clinical trials RTOG Gr ≥2 GI toxicity. 5-yr PSA

relapse-free survival 83.2% without any

local recurrence.

Prostate Cancer: Hypofractionation studies

Author Study Patient criteria Study details Results

King Prospective N=41

Stanford

SBRT (CyberKnife)

36.25 Gy/ 5 fr/ 1 week


Biochemical control 100%

At 12 months, 78% achieved PSA nadir

RTOG Gr ≥3 rectal toxicity 4.8%

Friedland Prospective N=112

Naples

Feb2005-Dec

2006

SBRT (CyberKnife)

RT dose: 35-36 Gy/5 fr


3 patients had failure (two local and one

distant failure). 82% no erectile

dysfunction

Brachytherapy

Galalae Three centre

data

N=611

Localized

prostate cancer

HDR brachytherapy

combined with EBRT

5-yr PSA relapse-free survival were 96%,

88%, and 69% for favorable-,

intermediate-, and unfavorable-risk

patients

Prostate Cancer: Ultra-hypofractionation studies

Fullar et al, IJROBP 2008

Radiosurgery mimicking brachytherapy


Radiosurgery mimicking brachytherapy


Radiosurgery vs brachytherapy: Dosimetry

Radiosurgery vs brachytherapy: Dosimetry


Hossain et al, IJROBP 2010

SBRT vs IMRT : Dosimetry


SBRT vs IMRT : Dose distribution




SBRT: Early outcome of Ph II study (n=45)

SBRT: Early outcome of Ph II study (n=45)

SBRT: Clinical outcome (n=112)

Frieland et al, IJROBP 2009

Probability of maintaining erectile function

Robinson et al IJROBP 2002

King et al. IJROBP 2010

QOL: Sexual function domains

5 yr FU data with biochemical control & QOL function

QOL: Sexual function domains

King et al. IJROBP 2010

Aluwin J of Endourology 2010

Experiences from new centres

Aluwin J of Endourology 2010

Experiences from new centres

Stage Grade Treatment Treatment of recurrence

/ residual disease

Ta G1 TURBT + Immediate single

chemotherapy instillation with in

24 hrs of TURBT

Repeat TURBT

If sign of muscle

invasion consider

cystectomyG2-3

TURBT + Intravesicle therapyTcis G1-3

T1 G1-3

Superficial urinary Bladder

Author Study type Study details Results Remarks

van der

Werf-

Messing

Randomized

( n= 174)

Arm1: pre-OP RT

(30 Gy/15 fr) +

Nephrectomy

Arm 2:

Nephrectomy only

5 yr Survival:

50%

No difference between

Surgery alone and Pre-

OP RT + Surgery arm;

Increased resectability

in T3 disease

Juusela Randomized

(n=88)

Arm 1:

Nephrectomy alone

Arm 2: Pre OP RT

(33Gy; 2.2 Gy/Fr) +

Nephrectomy

5 yr Survival:

Arm 1: 63%

Arm 2: 47%

(p-value= NS)

No difference in

survival

Renal cell cancer: Pre-OP RT

Renal cell cancer: Post-OP RTAuthor Study type Study details Results Remarks

Kao GD Retrospective

(n=12)

Loco-regionally

advanced RCC

RT dose: 41.4- 63 Gy;

1.8-2 Gy/Fr

5 yr local control

rate 100%

High precision RT was used.

Acceptable toxicity profile.

Rabinovitch RA Prospective

Non-randomized

n=172;

year1978-88

Early (T1-2) localized

RCC

Treated with surgery

alone

7 yr actuarial loco-

regional failure 5%

30 pts had distant

metastasis

Adjuvant treatment may not

be useful in early RCCs

without nodal involvement.

Fugitt RB Randomized New Castle, United

Kingdom,

RT dose 55 Gy in 2.04

Gy/Fr

No survival

advantage with

PORT

4 patients died due to RT

induced hepatotoxicity

Kjaer M Randomized Copenhagen Renal

Cancer Study Group

Stage II/III RCC

RT dose 50Gy/20

fractions

No Survival

advantage with

PORT

44% had significant GI

complication

19% died due to RT induced

complications.

Sub-optimal radiation

therapy delivered

Author Study type Study details Results

Walsh L Prospective

n=12

Nude mice were injected

subcutaneously with A498 human

RCC cells.

RT dose: 48 Gy/3 fr(one per

week)

At 7 wks post-RT,

30% reduction in

volume

Beitler JJ Prospective

n=9

Medically inoperable RCC

SBRT

40 Gy/5 fr/1 week

Median FU 26.7 months

OS: 46% (4/9)

Loco-regional failure:

11% (1/9)

Wersall PJ Prospective

n=8

Medically inoperable RCC

SBRT

40 Gy/5 fr/1 week

Median FU 26.7 months

median OS: 58

months

loco-regional control

87%

Renal cell cancer: SBRT

Urological malignancies: Role of SBRT

Conclusion

- Hypofractionated RT / SBRT is an option in low risk carcinoma prostate

- Short course RT is equally effective compared with conv RT

- Short course RT is well tolerated and have similar gr 3/4 toxicities.

- Biochemical control is impressive in short term follow up data

-Need long term follow up data

- Radiosurgery is an interesting option in RCC & metastatic disease.

Indications of Cyberknife: Intracranial lesions

• Benign intracranial tumours

- Acustic neuromas

- Schwannomas

- Small meningiomas

- Chordomas

- Residual low grade gliomas

- Atriovenous malformation (AVMs)

• High grade gliomas after recurrence / post RT residual disease.

Indications of Cyberknife:

Extra-cranial lesions

• Small (T1) primary lung cancer

• Localized prostate cancer.

• Inoperable pancreatic cancer.

• Localized gall bladder cancer.

• Recurrent head and neck cancer in primary site or node.

• Residual disease/ boost treatment in nasopharynx/PNS region.

Indications of Cyberknife: Metastatic disease

• Solitary (or Oligo) brain metastasis.

• Solitary (or Oligo) lung metastasis.

• Solitary (or Oligo) liver metastasis.

• Isolated bone metastasis.

Thank you

+91-9884234290

[email protected]

mailto:[email protected]

Health & Medicine

Cyber knife in urological malignancies