1

IMRT for Gynecologic IMRT for Gynecologic Malignancies:Malignancies:

The University of ChicagoThe University of ChicagoExperienceExperience

Bulent Aydogan, PhDBulent Aydogan, PhDThe University of ChicagoThe University of Chicago

BackgroundBackground�� RT has a long history in the treatment of RT has a long history in the treatment of

gynecologic malignancies, notably cervical gynecologic malignancies, notably cervical and endometrial cancerand endometrial cancer

�� The 1st gynecology patient was treated with The 1st gynecology patient was treated with RT a century agoRT a century ago

Gynecologic RTGynecologic RT

�� Highly efficacious and well tolerated Highly efficacious and well tolerated in most patientsin most patients

�� Excellent pelvic control particularly Excellent pelvic control particularly in early stage cervical and in early stage cervical and endometrial cancerendometrial cancer

�� Adjuvant RT improves outcome of Adjuvant RT improves outcome of women with high risk features women with high risk features following surgeryfollowing surgery

GYNGYN--IMRT RationaleIMRT Rationale�� Potential toxicities due to the treatment Potential toxicities due to the treatment

of considerable volumes of normal tissuesof considerable volumes of normal tissues�� Small bowelSmall bowel→→ diarrhea, SBO, enteritis, diarrhea, SBO, enteritis,

malabsorptionmalabsorption�� Rectum Rectum →→ diarrhea, proctitis, rectal bleedingdiarrhea, proctitis, rectal bleeding�� Bone Marrow Bone Marrow →→ ↓↓WBC, WBC, ↓↓platelets, anemiaplatelets, anemia�� Pelvic Bones Pelvic Bones →→ Insufficiency fractures, Insufficiency fractures,

necrosisnecrosis�� Reduction in the volume of normal tissues Reduction in the volume of normal tissues

irradiated with IMRT may thus irradiated with IMRT may thus ↓↓risk of risk of acute and chronic RT sequelaeacute and chronic RT sequelae

2

Gynecologic IMRTGynecologic IMRTflow chartflow chart

Patient selection

Simulation – Prone vs. Supine; Type of immobilization

Target and Tissue Delineation – Multiple imaging modalities↓

Treatment Planning/Optimization – Number of beams/orientation↓

Plan Evaluation – High conformity vs. dose homogeneity↓

Quality Assurance – Verification of calculated dose↓

Treatment Delivery/Verification – Verification scheme / IG

Imaging for treatment assessment - Tumor response / Adaptive approach

↓↓↓↓

↓↓↓↓

↓↓↓↓

↓↓↓↓

Patient SelectionPatient Selection

�� Poor candidatesPoor candidates�� Uncooperative patientsUncooperative patients�� Unable to tolerate Unable to tolerate ↑↑ time on the tabletime on the table

�� Markedly obese patients not idealMarkedly obese patients not ideal�� Inability to capture entire external contourInability to capture entire external contour�� Difficulties with daily setupDifficulties with daily setup�� Dosimetric benefits may be less in the Dosimetric benefits may be less in the

obeseobese**

*Ahamad et al. Int J Radiat Oncol Biol Phys 2002;54:42

Simulation and CT ScanningSimulation and CT Scanning

�� Patients in supine positionPatients in supine position�� Immobilized using a customized deviceImmobilized using a customized device�� Patient scanned from L2 to below Patient scanned from L2 to below

ischial tuberositiesischial tuberosities�� Oral, IV and rectal contrastOral, IV and rectal contrast

Immobilization•Immobilized supine•Upper and lower body alpha cradles indexed to the table

Mell LK, Roeske J, Mundt AJ.Gynecologic Tumors: Overview Chapter 23 IMRT: A Clinical Perspective BC Decker, Toronto 2005

University of Chicago

3

Others favor the proneposition

Data from the U Iowasuggest ↑ dosimetricbenefits with the pronePosition

*Adli et al .Red J 2003;57:230-238

University of Colorado

Schefter T, Kavanagh B.Cervical Cancer: Case Study. Chapter 23.1IMRT: A Clinical Perspective 2005

Simulation

Note: Not possible in patients treated with pelvic-inguinal IMRT (frog-leg position)

Helps delineate normal and target tissues

Oral, rectal and IV contrastBladder contrast not needed

IV contrast is important (vessels serve as surrogates for nodes)*With experience, IV contrast less needed

A vaginal marker is also placed(be careful not to distort)

Contrast AdministrationContrast Administration

Target DefinitionTarget Definition�� CTV CTV componentscomponents depend on the depend on the

pathologypathology�� In all patients:In all patients:

�� Upper Upper ½½ of the vaginaof the vagina�� Parametrial tissuesParametrial tissues�� Pelvic lymph nodes regions (common, Pelvic lymph nodes regions (common,

internal and external iliacs)internal and external iliacs)�� In cervical cancer and endometrial In cervical cancer and endometrial

cancer patients with positive cervical cancer patients with positive cervical involvementinvolvement�� include the presacral regioninclude the presacral region

PTV Bladder Larg e bowel

CTV Small bowel Rectal wall

postop erativ e RT defin iti ve RT

CTV and Normal TissuesCTV and Normal Tissues

P Georg, MD – Med University Vienna

4

Normal TissuesNormal Tissues�� Normal tissues delineated depends on the Normal tissues delineated depends on the

clinical caseclinical case�� In most cases, include:In most cases, include:

Small bowel, rectum, bladderSmall bowel, rectum, bladder�� In patients receiving concomitant or In patients receiving concomitant or

sequential chemotherapy, include the sequential chemotherapy, include the bone bone marrowmarrow

�� Others include the Others include the femoral headsfemoral heads�� Kidneys and liver included only if treating Kidneys and liver included only if treating

more comprehensive fieldsmore comprehensive fields

Normal TissuesNormal TissuesConsistency with contouringConsistency with contouring helps with helps with

DVH interpretation and outcome studiesDVH interpretation and outcome studies

�� RectumRectum: Outer wall (anus to the sigmoid : Outer wall (anus to the sigmoid flexure)flexure)

�� Small bowelSmall bowel: Outermost loops from the L4: Outermost loops from the L4--5 interspace5 interspace�� Include the colon above the sigmoid flexure as Include the colon above the sigmoid flexure as

well in the well in the ““small bowelsmall bowel”” volumevolume�� Bone marrowBone marrow: Intramedullary space of the : Intramedullary space of the

iliac crests iliac crests (EASY TO CONTOUR THE BONE)(EASY TO CONTOUR THE BONE)�� Stop at the top of the acetabulumStop at the top of the acetabulum�� Note that this approach ignores marrow in Note that this approach ignores marrow in

other pelvic bonesother pelvic bones

• Dip small bowel contour into concave CTV•↑ Conformity reducing small bowel dose

Jhingran A, et al. MD AndersonEndometrial Cancer:Case StudyChapter 23.2IMRT: A ClinicalPerspective BC Decker 2005

Small Bowel

Small BowelSmall Bowel Treatment PlanningTreatment Planning�� Expand CTV Expand CTV →→ PTV PTV

�� To account for setup uncertainty and organ To account for setup uncertainty and organ motionmotion

�� Appropriate expansion remains unclearAppropriate expansion remains unclear�� Various expansions have been used for Various expansions have been used for GynGyn

IMRT ranging from 0.5 to 1.5 cmIMRT ranging from 0.5 to 1.5 cm�� At the U of Chicago, At the U of Chicago, we use 1 cmwe use 1 cm

�� Less is known about normal tissue motionLess is known about normal tissue motion�� So we donSo we don’’t expand the normal tissues t expand the normal tissues �� Other centers, e.g. MD Anderson, routinely Other centers, e.g. MD Anderson, routinely

expand normal tissuesexpand normal tissues

5

Setup UncertaintiesSetup Uncertainties�� Digitized weekly setup films of 50 patientsDigitized weekly setup films of 50 patients�� Immobilization: Alpha cradle under legs and Immobilization: Alpha cradle under legs and

upper body with arms above head*upper body with arms above head*�� Measured setup position using imageMeasured setup position using image--

registration interface (Balter, et al.)registration interface (Balter, et al.)

σσLRLR = 3.2 mm= 3.2 mmσσSISI = 3.7 mm= 3.7 mmσσAPAP = 4.1 mm= 4.1 mm

Mundt, Roeske and Lujan. Intensity modulated radiation therapy in gynecologic malignancies. In Medical Dosimetry, June 2002.

Organ MotionOrgan Motion�� A concern in the region of the A concern in the region of the vaginal vaginal

cuffcuff�� Two approaches are being studied at our Two approaches are being studied at our

institution to address this:institution to address this:�� IGRT (Varian OBI unit)IGRT (Varian OBI unit)�� Vaginal immobilization (Vaginal immobilization (B. Aydogan, Int J Radiat

Oncol Biol Phys 65:266-73, 2006.)�� Now we simply avoid Now we simply avoid tight tight CTV volumes CTV volumes

and use a 1 cm CTVand use a 1 cm CTV→→PTV expansionPTV expansion�� Produces very generous volumes around the Produces very generous volumes around the

vaginal cuffvaginal cuff

Organ MotionOrgan Motion�� Using this approach,Using this approach, nono failures in thefailures in the

vaginal cuff have been seen in patientsvaginal cuff have been seen in patientstreated with adjuvant IMtreated with adjuvant IM--PRT at ourPRT at ourinstitution (>100 pts treated)institution (>100 pts treated)

�� Nonetheless, tighter volumes could resultNonetheless, tighter volumes could resultinin ↓↓ toxicitytoxicity

�� Tighter margins are also needed if higherTighter margins are also needed if higherthan conventional doses are usedthan conventional doses are used

MD AndersonMD Anderson’’ss““Integrated Target VolumeIntegrated Target Volume””

�� A creative solution to the organ motion A creative solution to the organ motion problem developed at MDAH?problem developed at MDAH?

�� Two planning scans: one with a full and one Two planning scans: one with a full and one with an empty bladderwith an empty bladder

�� Scans are then fusedScans are then fused�� An An integrated target volume integrated target volume ((InTVInTV) is ) is

drawn on the drawn on the full full bladder scan bladder scan (encompassing the cuff and parametria on (encompassing the cuff and parametria on bothboth scans)scans)

�� InTVInTV is expanded by 0.5 cm is expanded by 0.5 cm →→ PTVPTVInTVInTV

6

Normal Tissue Changes and Normal Tissue Changes and Organ MotionOrgan Motion

Week 3 scan Treatment planning scan

Bladder

Rectum

Small bowel

Rectum

Bladder

Bladde r and Rectal Volumes

0

20

40

60

80

100

120

140

160

0 1 2 3 4 5

Week

Rectum

Bladder

DVH Comparisons DVH Comparisons -- BladderBladder

0

20

40

60

80

100

0 20 40 60 80 100 120

Percent Dose

Planning

Week 1

Week 2

Week 3

Week 4

Week 5

DVH Comparisons DVH Comparisons -- RectumRectum

0

20

40

60

80

100

0 20 40 60 80 100 120

Percent Dose

Planning

Week 1

Week 2

Week 3

Week 4

Week 5

7

IMRT Planning and delivery IMRT Planning and delivery at the University of at the University of

ChicagoChicago�� Initial phase are completed with CORVUS Initial phase are completed with CORVUS

planning system planning system �� Currently we use Varian Eclipse and PinnacleCurrently we use Varian Eclipse and Pinnacle�� 77--9 co9 co--axial beam angles axial beam angles (equally spaced)(equally spaced)�� 120 Leaf MLC using 120 Leaf MLC using �� stepstep--andand--shoot mode onshoot mode ona Varian 2100 Exa Varian 2100 Ex

Treatment PlanningTreatment Planning�� Prescription dose: 45Prescription dose: 45--50.4 Gy50.4 Gy

�� 45 Gy in pts receiving vaginal brachytherapy45 Gy in pts receiving vaginal brachytherapy�� 50.4 Gy if external beam alone50.4 Gy if external beam alone

�� 1.8 Gy daily fractions 1.8 Gy daily fractions �� Given inherent inhomogeneity of IMRT Given inherent inhomogeneity of IMRT �� Avoids hot spots > 2 GyAvoids hot spots > 2 Gy

�� ““Dose paintingDose painting”” (concomitant boosting) (concomitant boosting) remains experimentalremains experimental�� Potentially useful in pts with high risk Potentially useful in pts with high risk

factors (positive nodes and/or margins)factors (positive nodes and/or margins)

Treatment Treatment PlanningPlanning

�� Increasing number of Increasing number of planning systems now planning systems now commercially availablecommercially available

�� Despite inherent Despite inherent differences, no one differences, no one system appears superiorsystem appears superior

�� Acceptable gynecologic Acceptable gynecologic IMRT plans have been IMRT plans have been produced on produced on allall major major planning systemsplanning systems

Acceptable UnacceptableConformity Good PoorPTV Coverage > 98% < 96%

Hot SpotsLocation Within CTV Edge of PTV

Preferably within GTV Rectal or bladderwalls in ICB region

Magnitude <10% (110% dose) >20% (110% dose)0% (115% dose) >2% (115% dose)

Cold SpotsLocation Edge of PTV Within CTV or GTVMagnitude <1% of the total dose >1% of the dose

IMIM--WPRT Plan OptimizationWPRT Plan OptimizationCurrent PTVCurrent PTV--Specific CriteriaSpecific Criteria

8

A more difficult question is whatmakes a normal tissue DVHacceptable.

IM-WPRT plans achieve betternormal tissue DVHs than WPRT plans. But how good does a normal tissue DVH need to be?

The answer is not clear

IMIM--WPRT Plan OptimizationWPRT Plan OptimizationNormal Tissue Specific CriteriaNormal Tissue Specific Criteria

DVH Acceptance Criteria for Small Bowel

Dosimetric analysis of acute GI toxicity in our Gyne IMRT pts was performedOn multivariate analysis, the strongest predictor of acute GI toxicity was the small bowel volume receiving the prescription dose or higher (SBvol100%)

Roeske et al.Radiother Oncol 2003;69:201-7.

2.3

100

4101

1

+

=

V

NTCP

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 100 200 300 400 500 600

Volu me (cc)

NTCP Analysis ofNTCP Analysis ofGynecologic IMRT PatientsGynecologic IMRT Patients

Roeske et al. Radiother Oncol Roeske et al. Radiother Oncol 2003;69:2012003;69:201--77..

ConventionalPelvic RT

IMRT

Isodose Distribution Isodose Distribution ComparisonComparison

PTV

100% 70%

PTV

100% 70%

9

Small Bowel

0

20

40

60

80

100

0 20 40 60 80 100 120

Percent Dose

Conv

IMRT

Absolute Volume (cc) of SBRReceiving 45 Gy

0

200

400

600

800

1000

1200

1 2 3 4 5 6 7 8 9 10

Patient Number

Conv

IMRT

IMIM--WPRT WPRT Planning StudiesPlanning Studies

↓↓Volume Receiving Prescription DoseVolume Receiving Prescription DoseAuthorAuthor BowelBowel BladderBladder RectumRectumRoeskeRoeske ↓↓50%50% ↓↓23%23% ↓↓23%23%AhamadAhamad ↓↓4040--63%*63%* NSNS NSNSChenChen ↓↓70%70% ↓↓**** ↓↓****SelvarajSelvaraj ↓↓51%***51%*** ↓↓31%***31%*** ↓↓66%***66%***

*dependent on PTV expansion used*dependent on PTV expansion used**data not shown**data not shown***reduction in percent volume receiving 30 Gy or higher***reduction in percent volume receiving 30 Gy or higher

Quality AssuranceQuality Assurance

Prior to (and throughout) treatment, rigorous QA is Prior to (and throughout) treatment, rigorous QA is essentialessential

10

QAQA�� Dose verificationDose verification

�� Ion chamber, diode arrays, film, or MU Ion chamber, diode arrays, film, or MU calculation.calculation.

�� Verify setup accuracy on day 1 and then Verify setup accuracy on day 1 and then weekly with orthogonal xweekly with orthogonal x--ray filmsray films

�� Role of daily CBCT is still not clear Role of daily CBCT is still not clear �� Special QA problem is that field sizes Special QA problem is that field sizes

may exceed MLC travel limits may exceed MLC travel limits �� Fields must be split into Fields must be split into ≥≥ 22 carriage carriage

movementsmovements

Kamat h S et al. Med Phys 2004;31:3314Hong L et al. Int J Radiat Oncol Bio l Phys 2002;54:278

�� 14 cervical cancer pts14 cervical cancer pts�� MRI before RT and after 30 GyMRI before RT and after 30 Gy�� 46% 46% ↓↓GTVGTV

Impact of Tumor Regression Impact of Tumor Regression in Cervical Cancer Patientsin Cervical Cancer Patients

Van de Bunt et al. Int J Radiat Oncol Biol Phys 64(1):189-96, 2006.

Bladder

Rectum

Tumor

Bladder

Tumor

Rectum

PrescriptionIsodoseWeek 1 Week 3

TumorsShrinkPlan

adapts

Clinical ExperienceClinical Experience�� Between 2/00 and 7/05, >150 women were Between 2/00 and 7/05, >150 women were

treated with IMtreated with IM--WPRT in our clinicWPRT in our clinic�� Most had cervical cancer, primarily stage Most had cervical cancer, primarily stage

IBIB�� Most underwent definitive RT and, in Most underwent definitive RT and, in

stages IB2stages IB2--IIIB, concomitant cisplatinIIIB, concomitant cisplatin--based chemotherapybased chemotherapy

�� Endometrial cancer patients were treated Endometrial cancer patients were treated followingfollowing primary surgeryprimary surgery

�� ICB was administered in ~50% of women ICB was administered in ~50% of women following IMfollowing IM--WPRTWPRT

Mundt, Roeske, et al. Gyne Oncol 82(3): 456-463, 2001.Mundt et al. Int J Radiat Oncol Biol Phys 52(5):1330-1337, 2002.

11

Clinical ExperienceClinical Experience

�� How do results compare to conventional How do results compare to conventional treatments?treatments?

�� Acute GI toxicities (Grade 2)Acute GI toxicities (Grade 2)�� WPRT: WPRT: 91%91%�� IMIM--WPRT:WPRT: 60%60% p = 0.002p = 0.002

�� Acute GU toxicities (Grade 2)Acute GU toxicities (Grade 2)�� WPRT:WPRT: 20%20%�� IMIM--WPRT:WPRT: 10%10% p = 0.22p = 0.22

Mundt et al. Int J Radiat Oncol Biol Phys 52(5):1330-1337, 2002.

Acute GI toxicity in IMAcute GI toxicity in IM--WPRT Patients vs. WPRTWPRT Patients vs. WPRT

0

10

20

30

40

50

60

70

80

90

100

Grade 0 Grade 1 Grade 2 Grad e 3

IM-WPRTWPRT

ChronicChronic GI ToxicityGI Toxicity

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

0 1 2 3

IM-WPRTWPRT

On multivariate analysis controlling for age, chemo, stage and site,IMRT remained statistically significant ( p = 0.01; odds ratio 0.16, 95% confidence interval 0.04, 0.67)

Cervical CancerKochanski J, Mundt AJ. ASCO (2004) 34 stage I-II cervical cancer pts 21 intact uterus, 13 postoperative Median follow-up = 26.2 months3-year actuarial pelvic control = 92%

Endometrial CancerKnab B, Mundt AJ. ASTRO (2004) 31 stage I-III endometrial cancer pts treated postoperativelyMedian follow-up = 24.1 months3-year actuarial pelvic control = 100%

Excellent Pelvic Control RatesExcellent Pelvic Control Rates

12

Pelvic ControlPelvic Control�� While encouraging, followWhile encouraging, follow--up remains up remains

relatively short and the number of relatively short and the number of patients treated remains smallpatients treated remains small

�� Only with longer followOnly with longer follow--up and larger up and larger patient cohorts can more definitive patient cohorts can more definitive statements be madestatements be made

�� Cooperative groups (RTOG, GOG) are Cooperative groups (RTOG, GOG) are currently developing protocols to currently developing protocols to evaluate IMRT in gynecology patientsevaluate IMRT in gynecology patients

Future DirectionsFuture Directions

�� Bone marrow sparing IMRTBone marrow sparing IMRT�� IGRT and adaptive radiotherapy in IGRT and adaptive radiotherapy in

GYNGYN-- IMRTIMRT�� IMRT as a replacement of or IMRT as a replacement of or

complimentary to complimentary to brachytherapybrachytherapy

ConclusionsConclusions�� IMRT is a useful means of reducing the IMRT is a useful means of reducing the

volume of normal tissues irradiated in volume of normal tissues irradiated in gynecologic patients receiving WPRTgynecologic patients receiving WPRT

�� Our initial evaluation indicate a significant Our initial evaluation indicate a significant reduction in GI toxicity relative to patients reduction in GI toxicity relative to patients receiving conventional therapyreceiving conventional therapy

�� Continued followContinued follow--up and critical evaluation are up and critical evaluation are required to validate the long term merits of required to validate the long term merits of this approachthis approach

What about the negatives?What about the negatives?

�� IMRT results in higher volumes of normal IMRT results in higher volumes of normal tissue receiving lower dosestissue receiving lower doses

�� Increased MUs result in higher total body Increased MUs result in higher total body dosesdoses

�� Target and tissue delineation are Target and tissue delineation are timetime--consumingconsuming

�� LongLong--termterm followfollow--up is not available assessing up is not available assessing tumor control and tumor control and unexpectedunexpected sequelaesequelae

�� Clinical data are available from only one Clinical data are available from only one institution and while prospective no institution and while prospective no randomized comparisons have been performedrandomized comparisons have been performed

13

AcknowledgementsAcknowledgements

�� JJ RoeskeRoeske, PhD , PhD –– Loyola University Loyola University �� AJ AJ MundtMundt, MD , MD –– UnivUniv of California, San of California, San

DiegoDiego�� LK LK MellMell, MD , MD –– UnivUniv of California, San Diegoof California, San Diego�� P Georg, MD P Georg, MD –– Med University ViennaMed University Vienna�� X. Allen Li, PhD X. Allen Li, PhD –– Med College of WisconsinMed College of Wisconsin�� RR MiralbellMiralbell, MD , MD –– InstitutoInstituto OncologicoOncologico

TeknonTeknon, Barcelona and , Barcelona and HopitauxHopitauxUniversitairesUniversitaires, Geneva Switzerland, Geneva Switzerland

AcknowledgementsAcknowledgements

Tuning StructuresTuning Structures�� An anterior structure (An anterior structure (AVOIDAVOID) to ) to

reduce dose to the small bowelreduce dose to the small bowel�� AA SHELLSHELL around the PTV to force around the PTV to force

conformityconformity��First a 0.5 cm expansion is made on the First a 0.5 cm expansion is made on the

PTV (PTV (GAPGAP))��The SHELL is then a 2 cm expansion The SHELL is then a 2 cm expansion

around the GAParound the GAP�� A posterior structure (A posterior structure (RectumRectum--PTVPTV) to ) to

reduce the dose to the rectumreduce the dose to the rectum