Imrt In Gynecologic Malignancies
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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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0 10 20 30 40 50Dose (Gy)
Volu
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BMSparing-IM-WPRT4 Field Box
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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100
Grade 0 Grade 1 Grade 2 Grade 3
IM-WPRTWPRT
40 ptsCervical and Uterine PtsIM-pelvic RT +/- Brachy40 matched conventional pts
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0 100 200 300 400 500 600
Volume (cc)
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
0%
10%
20%
30%
40%
50%
60%
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
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; 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
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