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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