IGRT for Cervical Cancer Feb 8 2013 920A

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IGRT for Gyn Cancer?:

IGRT for Gyn Cancer? Akila N. Viswanathan, MD MPH Brigham and Women ’ s/Dana-Farber Cancer Center Harvard Medical School

Why use IGRT in Gyne?:

Why use IGRT in Gyne? Decrease toxicity Dose escalation Most important area for IGRT is in image guided brachytherapy

Major Issues with IMRT/IGRT:

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 :

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

PowerPoint Presentation:

Mobile uterus, Cervix, Normal Tissues

PowerPoint Presentation:

Decrease tumor size @1cm/week

Uterus Contouring :

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 CT Beadle et al IJROBP 2009;73:235-41 :

Movement of cervix on CT Beadle 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 :

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:

In addition to movement, must account for errors in contouring

PowerPoint Presentation:

RTOG consensus on contouring the CTV for intact cervix patients

Background & Aim:

( 12 /10) Background & Aim More conformal radiotherapy  a ccurate target definition important Cervix Cancer Clinical Target Volume (CTV) definitions variable Aim: Evaluate the variability in CTV delineation in preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group (RTOG). 4F pelvis RT IMRT

Methods & Materials:

( 13 /10) Methods & Materials 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 available Participants asked to contour: GTV Cervix (if seen) Uterus Upper vagina (3cm) Parametria Online (ITC RRT; Washington U) or on participant ’ s treatment planning software. Fig 1. Sample images (sagittal & axial) from clinical case. Figure 1


( 14 /10) Results Structure Sensitivity (Avg ±SD) Specificity (Avg ±SD) Kappa measure * GTV 0.84 ±0.14 0.96 ±0.04 0.68 § Cervix 0.55 ±0.24 0.98 ±0.03 0.42 § Uterus 0.68 ±0.22 0.97 ±0.03 0.57 § Vagina 0.58 ±0.13 0.99 ±0.01 0.53 § Parametria 0.48 ±0.27 0.99 ±0.02 0.42 § * corrected for chance §p-value <0.0001 19 participants contoured on axial MR images Sagittal MR & axial CT images available for reference


( 15 /10) Results Kappa measure Level of Agreement 0.81 - 1.00 Almost perfect 0.61 - 0.80 Substantial 0.41 - 0.60 Moderate 0.21 - 0.40 Fair 0.01 - 0.20 Slight 0.00 No agreement above chance -1.00 Complete disagreement GTV Kappa = 0.68 Cervix Kappa = 0.42 Uterus Kappa = 0.57 Vagina Kappa = 0.53 Parametria Kappa = 0.42 (Landis JR, Koch GG. 1977)

Results – 95% agreement:

( 16 /10) Results – 95% agreement GTV Cervix Vagina Uterus Parametria CTV consensus

PowerPoint Presentation:

Specificity was high Greater certainty about what should NOT be included in CTV Sensitivity was moderate Greater difficulty determining the interface between various CTV components Challenging case: Extreme ante-version of uterus Ability to view sagittal images Substantial organ motion, deformation and tumor regression for this site is not addressed in this work.

PowerPoint Presentation:

Parametria & change depending on volume of bladder Courtesy of Karen Lim, Princess Margaret Hospital

Assessment of location:

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

Rectal Sparing :

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 :

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?:

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:

PET/CT Fusion Nodal Contour IMRT for Nodal boost 54-65 Gy

Post-operative PAN positive no residual LN (45 Gy):

Post-operative PAN positive no residual LN (45 Gy)

Vaginal recurrence:

Vaginal recurrence Pelvic LN+ 45 Gy region 65 Gy pelvic mass and LN+

SBRT as a boost:

SBRT as a boost Node recurrence, sidewall recurrence Higher normal tissue dose Long term complication rate HDR SBRT

SBRT for Recurrent Cervix Ca:

SBRT for Recurrent Cervix Ca Dose Failure Deodato et al. Oncol Repo 22:415-419 1 pt w vaginal recurrence 30 Gy/6 fractions 7/11 FAIL 2 Grade 4 fistulae 1 Grade 4 ileus Guckenberger et al. Rad onc 94:53-59 7 central recurrences 50 Gy + 5 Gy x 3 Fx 7/10 FAIL

PowerPoint Presentation:

HDR SBRT SBRT HDR Images courtesy of A. Damato

Post-operative IMRT: RTOG Atlas www.rtog.org:

Post-operative IMRT: RTOG Atlas www.rtog.org

Image-Based Brachytherapy for Gynecologic Cancers :

Image-Based Brachytherapy for Gynecologic Cancers

Can IMRT replace brachytherapy? NO:

Can 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 After 45 Gy EBRT

Volume Based Treatment:

Volume Based Treatment Moves with patient Does not move with patient Difficult to adjust with response Brachytherapy IMRT

Brachytherapy is Necessary:

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 PC 4 y Survival Lanciano 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

PowerPoint Presentation:

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-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 MRI/CT compatible applicators inserted brachytherapy suite Secure fixation of applicator within pt (vaginal packing and perineal bar)

CT-Based Brachytherapy:

CT-Based Brachytherapy Rule out uterine perforation

CT-Based Brachytherapy:

CT-Based Brachytherapy Assess location and position of applicator relative to the uterus

PowerPoint Presentation:

bladder rectum Use of Contrast Drain bladder Clamp foley 60 cc of 10% hypaque contrast into bladder 50 cc barium rectum

Organs at Risk: Bladder, Rectum, Sigmoid, Small Bowel:

Organs at Risk: Bladder, Rectum, Sigmoid, Small Bowel Bladder Rectum

CT based targets vs. MR-imaging:

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

CT Gyne Brachy Improves Outcomes: Prospective French STIC trial:

# Mode of treatment St Imaging During BT Median Follow up (years) Local control (%) Disease specific Survival (%) Overall Survival (%) Grade 3-4 Toxicity 705 IB-IIIB 2 76 BT and Sx Xray 92 87 95 14.6 89 BT and Sx CT 100 90 96 8.9 142 ChRT/BT and SX Xray 85 73 85 12.5 163 ChRT/BT and SX CT 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

External beam response:

Viswanathan ASTRO 9/25/08 Diagnosis MRI 1 st fraction External beam response

Similar OAR contours no significant differences Viswanathan et al. Int J Radiat Oncol Biol, 2005:

Similar OAR contours no 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

Brachytherapy exemplifies…:

Viswanathan ASTRO 11/3/09 Brachytherapy exemplifies… Point versus volume

3D Brachytherapy Outcomes:

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 :

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

Plan for each HDR fraction required Radioth Oncol 81:269, 2006:

Viswanathan ASTRO 9/25/08 Plan for each HDR fraction required Radioth Oncol 81:269, 2006

HDR/PDR Treatment Planning: Dose Optimization:

Viswanathan ASTRO 11/3/09 HDR/PDR Treatment Planning: Dose Optimization Standard plan Optimized plan

Practical implementation:

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

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