IMRT in Gynecologic MalignanciesArno J. Mundt MD

Professor and ChairDepartment of Radiation OncologyUniversity of California San Diego

La Jolla CA

BackgroundIntensity Modulated Radiation Therapy (IMRT)Computerized software used to conformthe dose to the shape of the target in 3D, thereby reducing the volume of normal tissues receiving high dosesBetter sparing of normal tissues should mean less acute and chronic toxicity

Inverse processTarget and normal tissues delineated on a planning CT Software used to deliver the dose to the target while minimizing dose to the normal tissuesAccomplished by dividing beams into small “beamlets”Intensity of each beamletindividually optimized

Red = high intensityGreen = moderate intensityYellow = low intensity

4 Field

IMRT

When cast into the patientHighly conformal dose distributionsare achieved

IMRTFirst conceived in the early 1960sClinical implementation had to await development of computerized software 1st patient treated in 1992 (prostate)*Nearly all centers in the USA now have IMRT capabilityIncreasingly available in Europe and Asia

*first gynecology patient treated in early 1997

IMRTBecoming standard in many tumor sites (prostate and head/neck cancers)Strong evidence including randomized clinical trials have demonstrated its benefitsSignificant reductions in acute and chronic toxicities (dermatitis, xerostomia, proctitis)Better tumor control ratesProstate IMRT outcomes equivalent to radical prostatectomy

What about Gynecology?

Growing in popularity2002 IMRT Survey- 15% respondents using IMRT in gynecology patients2004 IMRT Survey- 35% using IMRT in gynecology patients

4th most common site treatedMost rapidly growing IMRT site

Mell LK, Roeske JC, Mundt AJ. Survey of IMRT Use in the United States. Cancer 2003;98:204-211

Mell LK, Mundt AJ. Survey of IMRT Use in the USA- 2004Cancer 2005;104:1296

0%10%20%30%40%50%60%70%80%90%

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1992 1995 1998 2001 2004*Year *As of 8/04

Cancer2005;104:1296

Site % __Prostate 85% Head and Neck 80%CNS Tumors 64%Gynecology 35% Breast 28%GI 26%Sarcoma 20%Lung 22%Pediatrics 16%Lymphoma 12%

IMRT Practice Survey (2004)

Mell LK, Mundt AJ. Survey of IMRT Use in the USA- 2004Cancer 2005;104:1296

Site %Head and Neck 92%Prostate 81%CNS Tumors 56%Pediatrics 38%Gynecology 24%Recurrent/Palliative 24%Breast 21%GI 21%Lung 15%Lymphoma 7%

Disease Sites TreatedResident Survey

Malik R, Mundt AJ et al.Tech Cancer Res Treat 2005;4:303

Gynecologic IMRTRationale

Improved delivery of conventional doses↓Dose to normal tissuesSmall bowel, bladder, rectum, marrow

Dose escalation in high risk patientsNode positiveGross residual disease

Alternative/Replacement for BrachytherapyHeresy!Or is it?

Dosimetric (Planning) StudiesNumerous investigators have compared IMRT and conventional RTAll have shown a benefit to IMRTComparable or better target coverageImproved sparing of normal tissues

To evaluate IMRT as a replacement for conventional whole pelvic RT (WPRT)Our goals were:

To provide homogeneous dose coverage of the target tissues (PTV)↓volume of small bowel, rectum and bladder irradiated

Roeske JC, Mundt AJ et al.Int J Radiat Oncol Biol Phys 48:1613-1621, 2000

Chicago Study10 pts (5 cervical, 5 uterine)Contrast-enhanced planning CT scan (oral, IV, rectal contrast)Clinical target volume (CTV) = upper 1/2 of the vagina, uterus (if present), parametria, and regional lymph nodes (common/external/internal iliacs, presacral nodes)Roeske et al. Int J Radiat Oncol Biol Phys 48:1613-1621, 2000

Intensity Modulated Pelvic RT Planning Studies

↓Volume Receiving Prescription DoseAuthor Bowel Bladder RectumRoeske ↓50% ↓23% ↓23%Ahamad ↓40-63%* NS NSChen ↓70% ↓** ↓**Selvaraj ↓51%*** ↓31%*** ↓66%***

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

Roeske et al. Int J Radiat Oncol Biol Phys 2000;48:1613Ahamad et al. Int J Radiat Oncol Biol Phys 2002;54:42Heron et al. Gynecol Oncol 2003;91:39-45Chen et al. Int J Radiat Oncol Biol Phys 2001;51:332

Dosimetric IMRT Studies

Benefits also seen in patients treated with more comprehensive fields

Extended Field RTPortelance et al. Int J Radiat Oncol Biol Phys 2001;51:261Chen et al. Int J Radiat Oncol Biol Phys 2001;51:232

Pelvic Inguinal RTBeriwal et al. Int J Radiat Oncol Biol Phys 2006;64:1395Garofalo et al. RSNA 2002

Whole Abdominal RTHong et al. Int J Radiat Oncol Biol Phys 2002;54:278Duthoy et al. Int J Radiat Oncol Biol Phys 2003;57:1019

Extended Fields (Pelvic+Paraortic)

↓Volume Receiving Prescription DoseBowel Bladder Rectum

Versus 2 fields ↓61% ↓96% ↓71%

Versus 4 fields ↓60% ↓93% ↓56%

•10 advanced cervical cancer patients•IMRT compared with 2 and 4 field techniques•Comparable target coverage •Significant ↓volume of normal tissues irradiated

Portelance et al. Int J Radiat Oncol Biol Phys 2001;51:261

Pelvic-Inguinal Fields

• 9 vulvar pts• IMRT vs APPA plus electron fields• Volume of small bowel, rectum and bladder receiving ≥ 30 Gy reduced by 27%, 41% and 26%• No benefit for the femoral heads

Beriwal et al.Int J Radiat Oncol Biol Phys 2006;64:1395

Extended Fields (Whole Abdomen)MSKCC

• 10 endometrial cancer pts• IMRT vs conventional WART (with kidney blocks)• IMRT →↓dose to the bones and ↑target coverage with comparable kidney dose• Volume of pelvic bones irradiated ↓60% • Improved coverage of peritoneal cavity

Hong et al.Int J Radiat Oncol Biol Phys 2002;54:278-289

Gynecologic IMRTBone Marrow Sparing ApproachFocus on small bowel and rectumAdditional important organ is bone marrow40% total BM is in the pelvis (within the RT fields)↓Pelvic BM dose may ↑tolerance of concurrent chemotherapy and the chemotherapy at relapse

BM Sparing IM-WPRT

To evaluate the ability of IMRT to ↓volume of BM irradiated, conventional and IMRT plans compared in terms of the volume of BM irradiated Focused on the iliac crests

Lujan AE, Roeske JC, Mundt AJ. Int J Radiat Oncol Biol Phys 2003;57:516-521

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DVH DataDose (Gy) 4-field Box

(% BM volume)BM-sparing IM-WPRT

(% BM volume) p-value

10 95.13 99.01 < 0.003 15 94.6 91.9 0.101 20 89.3 78.8 < 0.001 30 56.2 37.6 < 0.001 40 43.7 17.0 < 0.001 45 33.6 6.8 < 0.001

Lujan et al.Int J Radiat Oncol Biol Phys 2003;57:516

100% 95% 90% 70% 50%

Isodose lines bend away from BM (crests)

Dosimetric (Planning) StudiesNumerous investigators have also demonstrated that IMRT may allow safe dose escalation in high risk patients

Exciting application is the use of IMRT to treat PET+ node using dose painting

Dose Escalation IMRT

A simultaneous integrated boost (SIB) to high risk sites , e.g. +nodes (45 Gy/1.8 pelvis + 56 Gy/2.24 Gy involved site)

Lujan AE, Mundt AJ, Roeske JC. Med Phys 2001;28:1262

• SIB technique to irradiate PA+ cervical cancer patients • PA region receives 50.4/1.53 daily fractions and the involved PA

nodes receives 59.4 Gy/1.8 Gy daily fractions

Mutic et al. (Wash U)Int J RadiatOncol Biol Phys 2003;55:28-35

Alternative/Replacement forBrachytherapy

Very contentious issueHighly conformal plans are possibleUnclear whether biologically equivalent

Roeske, Mundt et al.Med Physics 2000;27:1382

On average, total dose = 79 Gy (45 Gy pelvic RT + 34 Gy boost) possibleWith smaller margins, higher doses possible0.25 cm margin → 84 Gy or higher

Brachytherapy vs IMRTLow et al. (Washington U)Int J Radiat Oncol Biol Phys

52:1400, 2002

Applicator guided IMRT in place of brachytherapy

Applicator provides immobilization and spatial registration of the cervix, uterus and normal tissues

Treat using HDR schedules Top=IMRT, bottom=HDR brachy

Guerrero et al.Int J Radiat Oncol Biol Phys 2005;62:933

SIB approach45 Gy in 1.8 Gy fractions (pelvis)70 Gy in 2.8 Gy fractions (cervical tumor)

Radiobiologically ≈ 45 Gy + 30 Gy HDR (5 fx)Better bowel and bladder sparingShortens overall treatment to 5 weeks

Others have proposed using a simultaneous integrated boost (SIB)

Clinical Studies

Clinical StudiesIncreasing number of clinical studies suggest a benefit to IMRTReductions in acute and chronic toxicitySame or better tumor controlHowever, follow-up remains short and patient numbers are limited

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IM-WPRTWPRT

40 ptsCervical and Uterine PtsIM-pelvic RT +/- Brachy40 matched conventional pts

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NTCP AnalysisAcute GI Toxicity

Roeske JC, Mundt AJ et al. Radiother Oncol 2003;56:1354)

Beriwal et al.Int J Radiat Oncol Biol Phys 2006;64:139515 vulvar pts7 preop (46 Gy), 8 postop (50.4 Gy)Well tolerated (only 1 acute grade 3 toxicity)

Acute ToxicityPelvic/Inguinal IMRT

Grade1 2 3 4

GI 60% 20% 6% 0%GU 6% 13% 0% 0%Skin 26% 73% 0% 0%

Gerszten et al.Gynecol Oncol 2006;102:18222 cervical cancer pts45 Gy/1.8 Gy fractions + 55 Gy/2.2 Gyfractions to +PET nodesAll received concomitant cisplatinLow rates of acute toxicity

Acute ToxicityPelvic/Paraortic (Extended field) IMRT

Grade1 2 3 4

GI 38% 10% 0% 0%GU 24% 10% 0% 0%Skin 5% 10% 0% 0%

Salama J, Mundt AJ et al.Int J Radiat Oncol Biol Phys 2006;65:117013 pts (8 endometrial, 5 cervical)45 Gy/1.8 Gy fractions12 chemo (5 pre-RT, 5 concomitant, 5 post-RTNo grade 3 GU or GI acute toxicities

Acute ToxicityPelvic/Paraortic (Extended field) IMRT

Grade1 2 3 4

GI Diarrhea 15% 84% 0% 0%Nausea 38% 54% 0% 0%

GU Dysuria 15% 7% 0% 0%

Acute ToxicityGI GU

n g2 g3 g2 g3PelvisMundt 40 60% 0% 10% 0%Chen 33 24% 0% 12% 0%Beriwal 47 70% 0% 4% 0%

Pelvic-ParaorticSalama 13 84% 0% 7% 0%Beriwal 36 69% 3% 19% 3%Gerszten 22 10% 0% 10% 0%

Pelvic-InguinalBeriwal 15 20% 6% 13% 0%

Mundt et al. Red J 2002;52 1330 Beriwal et al. Red J 2006;64:1395Chen et al. Red J 2007;67:1438 Beriwal et al. Red J 2007;68:166Beriwal et al. Gyne Oncol 2006;102:1395 Gerszten Gyne Oncol 2006;102:182Salama et al. Red J 2006;65:1170

Hematologic Toxicity

Brixey C, Roeske JC, Mundt AJ.Int J Radiat Oncol Biol Phys 54:1388-93,

2002.

Acute hematologic toxicity also reduced with IMRT

A surprise finding comparing Conventional and IMRT pts

BM not intentionally spared. But it received less dosedue to highly conformal plans

Grade ≥ 2 WBC ToxicityWPRT versus IM-WPRT Patients

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RT Alone RT + Chemo

WPRTIM-WPRT

p = 0.82 p = 0.08Brixey et al. Int J Radiat Oncol Biol Phys 52:1388-93, 2002

IM-WPRT resulted ina lower rate of declineof WBC counts duringtherapy

Brixey C, Roeske J, Mundt AInt J Radiat Oncol Biol Phys 52:1388-93, 2002

BM-Sparing IMRTLed us to develop BM-sparing plans by intentionally sparing the iliac crests However, the iliac crests may not be the structures to avoid

Predictors of Hematologic Toxicity37 cervical cancer pts treated with IMRT plus Cisplatin (40 mg/m2/week)Predictors of hematologic toxicity and chemotherapy delivery:

Total Pelvic Bone Marrow V10 and V20 Lumbosacral Spine Bone Marrow V10 and V20

Volume of the iliac crests irradiated notcorrelated with hematologic toxicity

Mell LK, Roeske JC, Mundt AJInt J Radiat Oncol Biol Phys 2006;66:1356

Grade ≥ 2 Grade ≥ 2 Chemon WBC ANC Held

Pelvic BM V-10≤90% 18 11% 74% 16%>90% 19 74% 32% 48%

p < 0.01 p = 0.09 p = 0.08

Pelvic BM V-20≤75% 21 24% 14% 24%>75% 16 68% 25% 44%

p < 0.01 p = 044 p = 0.20

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

Beriwal et al.Gynecol Oncol 2006;102:195

47 endometrial cancer ptsPostop IMRT (39 pelvis, 8 pelvic+paraortic)Median follow-up = 20 months

3-year actuarial grade ≥2 toxicity = 3.3%

Chronic Toxicity

Grade1 2 3 4

GI 28% 0% 2% 0%GU 14% 0% 0% 0%

SBO

Chronic ToxicityGI GU

n g2 g3 g2 g3PelvisMundt 35 2.8% 0% 0% 0%Chen 33 0% 0% 0% 3%Beriwal 47 0% 0% 0% 0%

Pelvic-ParaorticBeriwal 36 2.7% 5.5% 0% 0%

Mundt et al. Red J 2003;56:1354Chen et al. Red J 2007;67:1438Beriwal et al. Gyne Oncol 2006;102:1395Beriwal et al. Red J 2006;64:1395

Tumor ControlVery little dataSingle institution experiencesShort followupBut promising

Cervical CancerPelvic

n FU Stage DFS ControlIntact CervixKochanski 44 23 m I-IIA 81% 93%

IIB-IIIB 53% 67%Beriwal 36 18 m IB-IVA 51% 80%

Postoperative CervixKochanski 18 21 m I-II (node+) 79% 94%Chen 35 35 m I-II (node+) NS 93%

Kochanski et al. Int J Radiat Oncol Biol Phys 2005;63:214Beriwal et al. Int J Radiat Oncol Biol Phys 2007;68:166Chen et al. Int J Radiat Oncol Biol Phys 2001;51:332

Endometrial CancerPelvic

n FU Stage DFS Control

Knab 31 24 m I-III 84% 100%

Beriwal 47 20 m I-III 84% 100%

Knab et al. Int J Radiat Oncol Biol Phys 2004;60:303Beriwal et al. Int J Radiat Oncol Biol Phys 2006;102:195

CurrentResearch Directions

Guidelines/Consensus

Multi-institutional Trials

Image-Guidance

Clinical TrialsImportant to move from single institution to multi-institutional, prospective clinical trials

Ideally, multi-national studies given incidence of cervical cancer outside of USA

RTOG 0418Preliminary Results

ASTRO 200858 patients enrolled (25 centers)28% Grade ≥ 2 acute toxicity, primarily GastrointestinalMajority of CTVs drawn per protocol

Tata Memorial HospitalMumbai India

Phase II randomized trial (ongoing)Conventional RT vs IMRTTo date, 58 Cervical Cancer ptsGrade 2 or higher GI, GU, neutropenia

Conventional: 28%, 10% and 10%IMRT: 14%, 3%, and 3%

14 month median followup:No difference in response or tumor control

Guidelines/ConsensusLittle consensus exists on howgynecologic IMRT should be planned and deliveredHampers widespread implementationHampers development of multi-institutional clinical trials

Controversial IssuesOptimal positioning (prone vs supine)CTV components (?whole uterus in early stage patients)CTV delineationOptimal CTV-PTV marginOrgan motion issuesWhich normal tissues should be avoided? Optimal beam configuration. Optimal beam energy.Et cetera, et cetera…..

Example: PositioningUniversity of ChicagoUCSD

MD Anderson

University of Colorado

RTOG-GOG-ESTRO-NCIC Consensus Conference

Consensus conference on target designJune 2005CTV in the postoperative cervix or uterine patientGuideline for the current RTOG trialAtlas on RTOG websitePublished in the Red Journal

Most exciting area of research:image-guided IMRT

StandardRT W

ALL

IMRT

Advances in Gynecologic RT

Benefits

Key to Further Advancements

IMRT

IG-IMRT

Thank You