igrt for cervical cancer feb 8 2013 920 a cancer ci 2013

IGRT for Gyn Cancer?

Akila N. Viswanathan, MD MPHBrigham and Women’s/Dana-Farber

Cancer CenterHarvard Medical School

Why use IGRT in Gyne?

• Decrease toxicity

• Dose escalation

• Most important area for IGRT is in image guided brachytherapy

Major Issues with IMRT/IGRT

• Need for continual replanning given rapid regression of tumor

• High margin for error with tight margins

• Increase in integral dose

• Longer treatment times

Indications for IMRT/IGRT Cervix

• Nodal involvement (pelvic or PAN) – Maximize boost dose

• Para-aortic node treatment– Reduce small bowel dose

• Boost sidewall in region inaccessible to brachytherapy

• Recurrence in radiated area (re-irradiation)• NOT for routine treatment• NOT a replacement for brachytherapy

Mobile uterus, Cervix, Normal Tissues

Decrease tumor size @1cm/week

Uterus Contouring

• ? Include whole uterus

−Account for motion?

−Varies with bladder filling

−Hard to know where cervix ends and uterus begins

Movement of cervix on CTBeadle et al IJROBP 2009;73:235-41

• Center of the cervix:– 2.1 cm superior-inferior – 1.6 cm anterior-posterior– 0.82 right-left lateral

Mean maximum changes in the perimeter of the cervix:

2.3 cm and 1.3 cm in the superior and inferior

1.7 cm in the anterior, 1.8 cm in the posterior

0.76 and 0.94 cm in the right and left lateral

Movement on CT

• Haripotepornkul NH, Nath SK, Scanderbeg D, Saenz C, Yashar CM. Evaluation of intra- and inter-fraction movement of the cervix during intensity modulated radiation therapy. Radiother Oncol 2011;98:347-51

• Tyagi N, Lewis JH, Yashar CM, et al. Daily online cone beam computed tomography to assess interfractional motion in patients with intact cervical cancer. Int J Radiat Oncol Biol Phys 2011;80:273-80

• Within and between radiation treatments, cervical motion averaged approximately 3mm in any given direction with maximal movement of the cervix up to 18 mm from baseline

In addition to movement, must account for errors in

contouring

RTOG consensus on contouring the CTV for intact cervix patients

(12/10)

Background & AimBackground & Aim• More conformal radiotherapy More conformal radiotherapy accurate target definition accurate target definition

important important – Cervix Cancer Clinical Target Volume (CTV) definitions

variable

• Aim: Evaluate the variability in CTV delineation in Aim: Evaluate the variability in CTV delineation in preparation for a Phase 2 clinical trial being planned preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group (RTOG). by the Radiation Therapy Oncology Group (RTOG).

4F pelvis RT IMRT

(13/10)

Methods & MaterialsMethods & Materials• Clinical Case: Clinical Case:

– 35yo G4P3 – clinical stage 1B poorly differentiated

adenocarcinoma of cervix. – No adenopathy or metastatic disease seen on

staging investigations. – MRI report confirms no parametrial, uterosacral

ligament or myometrial invasion. • MR & CT data sets made availableMR & CT data sets made available• Participants asked to contour: Participants asked to contour:

– GTV– Cervix (if seen)– Uterus– Upper vagina (3cm)– Parametria

• Online (ITC RRT; Washington U) or on Online (ITC RRT; Washington U) or on participantparticipant’’s treatment planning software.s treatment planning software.

Fig 1. Sample images (sagittal & axial) from clinical case. Figure 1

(14/10)

ResultsResults

StructureStructureSensitivitySensitivity

(Avg(Avg±SD)±SD)

SpecificitySpecificity(Avg(Avg±SD)±SD)

Kappa Kappa measuremeasure**

GTVGTV 0.840.84±0.14±0.14 0.960.96±0.04±0.04 0.680.68§§

CervixCervix 0.550.55±0.24±0.24 0.980.98±0.03±0.03 0.420.42§§

UterusUterus 0.680.68±0.22±0.22 0.970.97±0.03±0.03 0.570.57§§

VaginaVagina 0.580.58±0.13±0.13 0.990.99±0.01±0.01 0.530.53§§

ParametriaParametria 0.480.48±0.27±0.27 0.990.99±0.02±0.02 0.420.42§§

*corrected for chance §p-value <0.0001

• 19 participants contoured on axial MR images

•Sagittal MR & axial CT images available for reference

(15/10)

ResultsResults

Kappa measure

Level of Agreement

0.81 - 1.000.81 - 1.00 Almost perfectAlmost perfect

0.61 - 0.800.61 - 0.80 SubstantialSubstantial

0.41 - 0.600.41 - 0.60 ModerateModerate

0.21 - 0.400.21 - 0.40 FairFair

0.01 - 0.200.01 - 0.20 SlightSlight

0.000.00 No agreement No agreement above chanceabove chance

-1.00-1.00 Complete Complete disagreementdisagreement

GTVGTV

Kappa = 0.68Kappa = 0.68

CervixCervix

Kappa = 0.42Kappa = 0.42

UterusUterus

Kappa = 0.57Kappa = 0.57

VaginaVagina

Kappa = 0.53Kappa = 0.53

ParametriaParametria

Kappa = 0.42Kappa = 0.42

(Landis JR, Koch GG. 1977)

(16/10)

Results – 95% agreementResults – 95% agreement

GTVGTV

CervixCervix

VaginaVagina

UterusUterus

ParametriaParametriaCTV CTV

consensusconsensusCTV CTV

consensusconsensus

• Specificity was high Specificity was high –Greater certainty about what should NOT

be included in CTV• Sensitivity was moderateSensitivity was moderate

–Greater difficulty determining the interface between various CTV components

• Challenging case: Challenging case: –Extreme ante-version of uterus –Ability to view sagittal images

• Substantial organ motion, deformation and Substantial organ motion, deformation and tumor regression for this site is not tumor regression for this site is not addressed in this work.addressed in this work.

Parametria & change depending on volume of bladder

Courtesy of Karen Lim, Princess Margaret Hospital

Assessment of location

• Ultrasound: imprecise

• kV imaging: rough estimate

• Cone beam CT: Intensive resource utilization

IMRT/IGRT

• No clear outcome benefit in cervix ca or postop endometrial cancer

• Greatest potential benefit in nodal recurrence

• May be dangerous due to need to include presacral nodes (mesorectal), uterosacral ligaments, and internal iliac nodes

• Rectal filling may vary

• NOT recommended

Rectal Sparing

Definitive Contouring

• Consider a CTV that includes the uterus/cervix, parametrial tissues, vagina, and pelvic nodes, (common, internal & external, obturator, and iliacs, presacral nodes) with exclusion only of small bowel and some bladder and sigmoid

• Need @3cm margin on CTV for uterine PTV; 1.5 cm on CTV cervix for PTV

• No sparing of rectum or posterior bladder; potential sparing of small bowel with para-aortic nodal field

Is IMRT/IGRT Ready for Prime Time in the Therapy of Cervical

Cancer?• For post-operative therapy – maybe

– Still need prospective verification of targets (RTOG 0418)

– Rectal movement remains a concern• For definitive therapy in cervical cancer – No

• Organ motion and volume changes during therapy remain a significant issue

• For para-aortic nodes, spare small bowel• Re-irradiation – unknown sequelae

PET/CT Fusion Nodal Contour

IMRT for Nodal boost 54-65 Gy

Post-operative PAN positiveno residual LN (45 Gy)

Vaginal recurrence

• Pelvic LN+• 45 Gy region• 65 Gy pelvic mass

and LN+

SBRT as a boost

• Node recurrence, sidewall recurrence

• Higher normal tissue dose

• Long term complication rateHDR SBRT

SBRT for Recurrent Cervix Ca

Dose FailureDeodato et al.Oncol Repo 22:415-419

1 pt w vaginal recurrence

30 Gy/6 fractions 7/11 FAIL2 Grade 4 fistulae1 Grade 4 ileus

Guckenberger et al. Rad onc 94:53-59 7 central recurrences

50 Gy + 5 Gy x 3 Fx 7/10 FAIL

HDR SBRT

SBRTHDR

Images courtesy of A. Damato

Post-operative IMRT: RTOG Atlaswww.rtog.org

Image-Based Brachytherapy for Gynecologic Cancers

Can IMRT replace brachytherapy? NOCan IMRT replace

brachytherapy? NO

• Complex internal organ motion– Brachy fixed to target

• Tumor response• The proximity of

critical structures leaves little room for error in EBRT planning

• Complex internal organ motion– Brachy fixed to target

• Tumor response• The proximity of

critical structures leaves little room for error in EBRT planning

After 45 Gy EBRT

Volume Based TreatmentVolume Based Treatment

Moves with patientMoves with patient Does not move with patientDifficult to adjust with responseDoes not move with patientDifficult to adjust with response

BrachytherapyBrachytherapy IMRTIMRT

Brachytherapy is Necessary• Tumor control probability correlated

with RT dose and cervix ca volume Fletcher, Shukovsky J Radiol Electrol 56:383-400, 1975

External beam only External Beam + brachytherapy

4 y PC4 y SurvivalLanciano JROBP 20:95, 1991

45%19%

67%46%

Local Control Montana Cancer 57:148, 1986

40% 52%

Ultrasound

• Suspected uterine preforation

• Retroverted uterus• Absence of

endocervical canal• Extreme

anteversion of uterus

Viswanathan ASTRO 9/25/08

Posterior placement

Proper placement

What might appear acceptable on Xray, may not be acceptable in 3D

CT-Based Brachytherapy

• CT-simulators available in most radiation oncology departments

• Easy transition from film-based dosimetry to CT-based dosimetry

MRI/CT Compatible Applicators •MRI/CT compatible applicators inserted brachytherapy suite

Secure fixation of applicator within pt

(vaginal packing and perineal bar)

CT-Based Brachytherapy

• Rule out uterine perforation

CT-Based Brachytherapy• Assess location and position of

applicator relative to the uterus

bladder

rectum

Use of ContrastDrain bladder

Clamp foley

60 cc of 10% hypaque contrast into bladder

50 cc barium rectum

Organs at Risk:Bladder, Rectum, Sigmoid, Small

Bowel

BladderRectum

CT based targets vs. MR-imaging

• GTV – T2 bright areas

• HR-CTV – cervix + visible/palpable disease at brachy

• IR-CTV – 1 cm margin around HR-CTV + initial sites of involvement

• CT definitions:

• CT-CTV – 3cm above applicator

• CE (Clinical exam)-CTV – includes vaginal extension

GTVHR CTV

IR CTV

GYN GEC ESTRO Recommendations (I) Radioth.Oncol. 2005, 74:235-245

#Mode of

treatmentSt

Imaging During

BT

Median Follow

up (years)

Local control

(%)

Disease specific

Survival (%)

Overall Survival (%) Grade 3-4

Toxicity

705IB-IIIB

2

76 BT and Sx Xray 92 87 95 14.6

89 BT and Sx CT 100 90 96 8.9

142ChRT/BT

and SXXray 85 73 85 12.5

163ChRT/BT

and SXCT 93 77 86 8.8

118 ChRT/BT Xray 74 55 65 22.7

117 ChRT/BT CT 78.5* 60 74 2.6

CT Gyne Brachy Improves Outcomes:Prospective French STIC trial

Viswanathan ASTRO 9/25/08

Diagnosis

MRI 1st fraction

External beam response

HR-CTV

Rectum

CT

MR

Bladder

Similar OAR contoursno significant differences

Viswanathan et al. Int J Radiat Oncol Biol, 2005

• Width larger on CT – Good for covering

parametrium– No issues with toxicity

• Height not determined on CT unless referring to an MRI– Estimate 3 cm on average– Always treat entire length

of tandem

Viswanathan ASTRO 11/3/09

Brachytherapy exemplifies…• Point versus volume

Viswanathan ASTRO 11/3/09

3D Brachytherapy Outcomes

• 145 patients• Historical

comparison• Significant ↑

– OS 53 to 64%– CSS 62 to 74%– Tumors > 5cm

• OS 28 to 58%

Pötter et al. Rad Oncol 2007

Physical-Biological Documentation of Gynecologic HDR BT

EQD2: BED/1.2

BED= nd(1+d/alpha-beta ratio)

BED: 5.5Gy x 5 (1 + 5.5/10)=42.625 Gy

EQD2: 42.625/1.2 = 35.5 Gy

Viswanathan ASTRO 9/25/08

Plan for each HDR fraction required

Radioth Oncol 81:269, 2006

Viswanathan ASTRO 11/3/09

HDR/PDR Treatment Planning:

Dose OptimizationStandard plan Optimized plan

Viswanathan ASTRO 11/3/09

Practical implementation• Standard plan mimics LDR loadings• Optimization superiorly – sigmoid/small bowel

– Treat entire tandem length +/- 1cm

• Optimization posteriorly - rectum– Watch dwell weight changes carefully

• Set to local rather than global• Change individual positions rather than regions

• Optimization anteriorly – bladder– Very high doses; no risk to tumor coverage

• “Over-coverage” versus “underdosage”

Summary

• IMRT – CAUTION– OK for nodal boost, PAN treatment,

recurrence– Not standard for primary cervical ca– NOT a substitute for brachytherapy– Use image guidance with brachytherapy to

reduce toxicity and maximize tumor coverage