1) Intensity modulated radiation therapy (IMRT) is a technique that uses computer software to conform the radiation dose to the shape of the tumor, reducing dose to surrounding normal tissues and decreasing toxicity. 2) Numerous studies have shown IMRT provides better sparing of the small bowel, bladder, and rectum compared to conventional radiation for gynecologic cancers. 3) IMRT may allow dose escalation to high risk sites or involved nodes while maintaining normal tissue doses. Some studies have also investigated using IMRT as an alternative to brachytherapy boosts. 4) Clinical studies suggest IMRT results in low rates of acute gastrointestinal and genitourinary toxicity compared to conventional radiation for

1. IMRT in Gynecologic Malignancies
Arno J. Mundt MD
Professor and Chair
Department of Radiation Oncology
University of California San Diego
La Jolla CA

2. Background
Intensity Modulated Radiation Therapy
(IMRT)
Computerized software used to conform
the dose to the shape of the target in
3D, thereby reducing the volume of
normal tissues receiving high doses
Better sparing of normal tissues should
mean less acute and chronic toxicity

3. Inverse process
Target and normal tissues
delineated on a planning CT
Software used to deliver the
dose to the target while
minimizing dose to the
normal tissues
Accomplished by dividing
beams into small “beamlets”
Intensity of each beamlet
individually optimized
Red = high intensity
Green = moderate intensity
Yellow = low intensity

4. IMRT
4 Field
When cast into the patient
Highly conformal dose distributions
are achieved

5. IMRT
First conceived in the early 1960s
Clinical implementation had to await
development of computerized software
1st patient treated in 1992 (prostate)*
Nearly all centers in the USA now have
IMRT capability
Increasingly available in Europe and
Asia
*first gynecology patient treated in early 1997

6. IMRT
Becoming standard in many tumor sites
(prostate and head/neck cancers)
Strong evidence including randomized
clinical trials have demonstrated its
benefits
Significant reductions in acute and
chronic toxicities (dermatitis, xerostomia,
proctitis)
Better tumor control rates
Prostate IMRT outcomes equivalent to
radical prostatectomy

7. What about Gynecology?
Growing in popularity
2002 IMRT Survey- 15% respondents using
IMRT in gynecology patients
2004 IMRT Survey- 35% using IMRT in
gynecology patients
4th most common site treated
Most 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- 2004
Cancer 2005;104:1296

8. 100% Cancer
2005;104:1296
90%
80%
Percent of Physicians
70%
60%
50%
40%
30%
20%
10%
0%
1992 1995 1998 2001 2004*
*As of 8/04
Year

9. IMRT Practice Survey (2004)
Site % __
Prostate 85%
Head and Neck 80%
CNS Tumors 64%
Gynecology 35%
Breast 28%
GI 26%
Sarcoma 20%
Lung 22%
Pediatrics 16%
Lymphoma 12%
Mell LK, Mundt AJ. Survey of IMRT Use in the USA- 2004
Cancer 2005;104:1296

10. Disease Sites Treated
Resident Survey
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%
Malik R, Mundt AJ et al.
Tech Cancer Res Treat 2005;4:303

11. Gynecologic IMRT
Rationale
Improved delivery of conventional doses
↓Dose to normal tissues
Small bowel, bladder, rectum, marrow
Dose escalation in high risk patients
Node positive
Gross residual disease
Alternative/Replacement for Brachytherapy
Heresy!
Or is it?

12. Dosimetric (Planning) Studies
Numerous investigators have compared
IMRT and conventional RT
All have shown a benefit to IMRT
Comparable or better target coverage
Improved sparing of normal tissues

13. 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

14. Chicago Study
10 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

15. Intensity Modulated Pelvic RT
Planning Studies
↓Volume Receiving Prescription Dose
Author Bowel Bladder Rectum
↓50% ↓23% ↓23%
Roeske
↓40-63%*
Ahamad NS NS
↓70% ↓** ↓**
Chen
↓51%*** ↓31%*** ↓66%***
Selvaraj
*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;48:1613
Ahamad et al. Int J Radiat Oncol Biol Phys 2002;54:42
Heron et al. Gynecol Oncol 2003;91:39-45
Chen et al. Int J Radiat Oncol Biol Phys 2001;51:332

16. Dosimetric IMRT Studies
Benefits also seen in patients treated with
more comprehensive fields
Extended Field RT
Portelance et al. Int J Radiat Oncol Biol Phys 2001;51:261
Chen et al. Int J Radiat Oncol Biol Phys 2001;51:232
Pelvic Inguinal RT
Beriwal et al. Int J Radiat Oncol Biol Phys 2006;64:1395
Garofalo et al. RSNA 2002
Whole Abdominal RT
Hong et al. Int J Radiat Oncol Biol Phys 2002;54:278
Duthoy et al. Int J Radiat Oncol Biol Phys 2003;57:1019

17. Extended Fields (Pelvic+Paraortic)
•10 advanced cervical cancer patients
•IMRT compared with 2 and 4 field techniques
•Comparable target coverage
•Significant ↓volume of normal tissues irradiated
↓Volume Receiving Prescription Dose
Bowel Bladder Rectum
↓61% ↓96% ↓71%
Versus 2 fields
↓60% ↓93% ↓56%
Versus 4 fields
Portelance et al.
Int J Radiat Oncol Biol Phys 2001;51:261

18. 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

19. 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

20. Gynecologic IMRT
Bone Marrow Sparing Approach
Focus on small bowel and rectum
Additional important organ is bone marrow
40% total BM is in the pelvis (within the RT
fields)
↓Pelvic BM dose may ↑tolerance of
concurrent chemotherapy and the
chemotherapy at relapse

21. 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

22. 100
90
80
70
Volume (%)
60
50
40
BMSparing-IM-WPRT
30
4 Field Box
20
10
0
0 10 20 30 40 50
Dose (Gy)

23. DVH Data
Dose (Gy) 4-field Box BM-sparing IM-WPRT p-value
(% BM volume) (% BM volume)
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

24. 100% 95% 90% 70% 50%
Isodose lines bend away from BM (crests)

25. Dosimetric (Planning) Studies
Numerous 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

26. 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

27. Mutic et al.
(Wash U)
Int J Radiat
Oncol Biol Phys
2003;55:28-35
• 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

29. Alternative/Replacement for
Brachytherapy
Very contentious issue
Highly conformal plans are possible
Unclear whether biologically equivalent

30. Roeske, Mundt et al.
Med Physics 2000;27:1382
On average, total dose = 79 Gy (45 Gy pelvic
RT + 34 Gy boost) possible
With smaller margins, higher doses possible
0.25 cm margin → 84 Gy or higher

31. Brachytherapy vs IMRT
Low 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

32. Others have proposed using a simultaneous
integrated boost (SIB)
Guerrero et al.
Int J Radiat Oncol Biol Phys 2005;62:933
SIB approach
45 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 sparing
Shortens overall treatment to 5 weeks

33. Clinical Studies

34. Clinical Studies
Increasing number of clinical studies
suggest a benefit to IMRT
Reductions in acute and chronic toxicity
Same or better tumor control
However, follow-up remains short and
patient numbers are limited

35. 40 pts
100
Cervical and Uterine Pts
90
IM-pelvic RT +/- Brachy
80
40 matched conventional pts
70
60
IM-WPRT
50
WPRT
40
30
20
10
0
Grade 0 Grade 1 Grade 2 Grade 3

36. NTCP Analysis
Acute GI Toxicity
1
1
NTCP =
0.9
3 .2
⎛ 410 ⎞
0.8
1+ ⎜ ⎟
⎜V ⎟
⎝ 100 ⎠
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 100 200 300 400 500 600
Volume (cc)
Roeske JC, Mundt AJ et al. Radiother Oncol 2003;56:1354)

37. Acute Toxicity
Pelvic/Inguinal IMRT
Beriwal et al.
Int J Radiat Oncol Biol Phys 2006;64:1395
15 vulvar pts
7 preop (46 Gy), 8 postop (50.4 Gy)
Well tolerated (only 1 acute grade 3 toxicity)
Grade
1 2 3 4
GI 60% 20% 6% 0%
GU 6% 13% 0% 0%
Skin 26% 73% 0% 0%

38. Acute Toxicity
Pelvic/Paraortic (Extended field) IMRT
Gerszten et al.
Gynecol Oncol 2006;102:182
22 cervical cancer pts
45 Gy/1.8 Gy fractions + 55 Gy/2.2 Gy
fractions to +PET nodes
All received concomitant cisplatin
Low rates of acute toxicity
Grade
1 2 3 4
GI 38% 10% 0% 0%
GU 24% 10% 0% 0%
Skin 5% 10% 0% 0%

39. Acute Toxicity
Pelvic/Paraortic (Extended field) IMRT
Salama J, Mundt AJ et al.
Int J Radiat Oncol Biol Phys 2006;65:1170
13 pts (8 endometrial, 5 cervical)
45 Gy/1.8 Gy fractions
12 chemo (5 pre-RT, 5 concomitant, 5 post-RT
No grade 3 GU or GI acute toxicities
Grade
1 2 3 4
GI Diarrhea 15% 84% 0% 0%
Nausea 38% 54% 0% 0%
GU Dysuria 15% 7% 0% 0%

40. Acute Toxicity
GI GU
n g2 g3 g2 g3
Pelvis
Mundt 40 60% 0% 10% 0%
Chen 33 24% 0% 12% 0%
Beriwal 47 70% 0% 4% 0%
Pelvic-Paraortic
Salama 13 84% 0% 7% 0%
Beriwal 36 69% 3% 19% 3%
Gerszten 22 10% 0% 10% 0%
Pelvic-Inguinal
Beriwal 15 20% 6% 13% 0%
Mundt et al. Red J 2002;52 1330 Beriwal et al. Red J 2006;64:1395
Chen et al. Red J 2007;67:1438 Beriwal et al. Red J 2007;68:166
Beriwal et al. Gyne Oncol 2006;102:1395 Gerszten Gyne Oncol 2006;102:182
Salama et al. Red J 2006;65:1170

41. Hematologic Toxicity
Acute hematologic toxicity also reduced with IMRT
A surprise finding comparing Conventional and IMRT
pts
BM not intentionally spared. But it received less dose
due to highly conformal plans
Brixey C, Roeske JC, Mundt AJ.
Int J Radiat Oncol Biol Phys 54:1388-93,
2002.

42. Grade ≥ 2 WBC Toxicity
WPRT versus IM-WPRT Patients
60%
50%
40%
WPRT
30%
IM-WPRT
20%
10%
0%
RT Alone RT + Chemo
p = 0.08
p = 0.82
Brixey et al. Int J Radiat Oncol Biol Phys 52:1388-93, 2002

43. IM-WPRT resulted in
a lower rate of decline
of WBC counts during
therapy
Brixey C, Roeske J, Mundt A
Int J Radiat Oncol Biol Phys
52:1388-93, 2002

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

46. Predictors of Hematologic Toxicity
37 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 not
correlated with hematologic toxicity
Mell LK, Roeske JC, Mundt AJ
Int J Radiat Oncol Biol Phys 2006;66:1356

47. Grade ≥ 2 Grade ≥ 2 Chemo
n 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

48. 90%
80%
70%
60%
50%
IM-WPRT
40%
WPRT
30%
20%
10%
0%
0 1 2 3
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)

49. Chronic Toxicity
Beriwal et al.
Gynecol Oncol 2006;102:195
47 endometrial cancer pts
Postop IMRT (39 pelvis, 8 pelvic+paraortic)
Median follow-up = 20 months
SBO
Grade
1 2 3 4
GI 28% 0% 2% 0%
GU 14% 0% 0% 0%
3-year actuarial grade ≥2 toxicity = 3.3%

50. Chronic Toxicity
GI GU
n g2 g3 g2 g3
Pelvis
Mundt 35 2.8% 0% 0% 0%
Chen 33 0% 0% 0% 3%
Beriwal 47 0% 0% 0% 0%
Pelvic-Paraortic
Beriwal 36 2.7% 5.5% 0% 0%
Mundt et al. Red J 2003;56:1354
Chen et al. Red J 2007;67:1438
Beriwal et al. Gyne Oncol 2006;102:1395
Beriwal et al. Red J 2006;64:1395

51. Tumor Control
Very little data
Single institution experiences
Short followup
But promising

52. Cervical Cancer
Pelvic
n FU Stage DFS Control
Intact Cervix
Kochanski 44 23 m I-IIA 81% 93%
IIB-IIIB 53% 67%
Beriwal 36 18 m IB-IVA 51% 80%
Postoperative Cervix
Kochanski 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;63:214
Beriwal et al. Int J Radiat Oncol Biol Phys 2007;68:166
Chen et al. Int J Radiat Oncol Biol Phys 2001;51:332

53. Endometrial Cancer
Pelvic
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;60:303
Beriwal et al. Int J Radiat Oncol Biol Phys 2006;102:195

54. Current
Research Directions
Guidelines/Consensus
Multi-institutional Trials
Image-Guidance

55. Clinical Trials
Important to move from single institution
to multi-institutional, prospective clinical
trials
Ideally, multi-national studies given
incidence of cervical cancer outside of
USA

57. RTOG 0418
Preliminary Results
ASTRO 2008
58 patients enrolled (25 centers)
28% Grade ≥ 2 acute toxicity, primarily
Gastrointestinal
Majority of CTVs drawn per protocol

58. Tata Memorial Hospital
Mumbai India
Phase II randomized trial (ongoing)
Conventional RT vs IMRT
To date, 58 Cervical Cancer pts
Grade 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

59. Guidelines/Consensus
Little consensus exists on how
gynecologic IMRT should be planned
and delivered
Hampers widespread implementation
Hampers development of multi-
institutional clinical trials

60. Controversial Issues
Optimal positioning (prone vs supine)
CTV components (?whole uterus in early
stage patients)
CTV delineation
Optimal CTV-PTV margin
Organ motion issues
Which normal tissues should be avoided?
Optimal beam configuration. Optimal beam
energy.
Et cetera, et cetera…..

61. Example: Positioning
University of Chicago
UCSD
MD Anderson
University of Colorado

62. RTOG-GOG-ESTRO-NCIC
Consensus Conference
Consensus conference on target design
June 2005
CTV in the postoperative cervix or uterine
patient
Guideline for the current RTOG trial
Atlas on RTOG website
Published in the Red Journal

66. Most exciting area of research:
image-guided IMRT

67. Advances in Gynecologic RT
Standard IMRT
W
RT
A
L
L
Benefits

68. Key to Further Advancements
IMRT
IG-IMRT

69. Thank You