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




4 Field


          When cast into the patient
          Highly conformal dose distributions
          are achieved
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
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
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
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
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
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
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?
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
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 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
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
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
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
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 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
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
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)
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
100% 95% 90% 70% 50%




Isodose lines bend away from BM (crests)
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
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
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
Alternative/Replacement for
        Brachytherapy
Very contentious issue
Highly conformal plans are possible
Unclear 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) possible
  With smaller margins, higher doses possible
  0.25 cm margin → 84 Gy or higher
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
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
Clinical Studies
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
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
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)
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%
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%
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%
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
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.
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
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
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
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
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
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)
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%
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
Tumor Control
Very little data
Single institution experiences
Short followup
But promising
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
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
Current
Research Directions
                Guidelines/Consensus

                Multi-institutional Trials

                Image-Guidance
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
RTOG 0418
       Preliminary Results
ASTRO 2008
58 patients enrolled (25 centers)
28% Grade ≥ 2 acute toxicity, primarily
Gastrointestinal
Majority of CTVs drawn per protocol
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
Guidelines/Consensus
Little consensus exists on how
gynecologic IMRT should be planned
and delivered
Hampers widespread implementation
Hampers development of multi-
institutional clinical trials
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…..
Example: Positioning
  University of Chicago
  UCSD




                          MD Anderson


University of Colorado
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
Most exciting area of research:
     image-guided IMRT
Advances in Gynecologic RT


Standard        IMRT
                           W
RT
                           A
                           L
                           L



Benefits
Key to Further Advancements

                     IMRT


                   IG-IMRT
Thank You

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IMRT Gynecologic Malignancies Reduces Toxicity</TITLE

  • 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
  • 28.
  • 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
  • 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
  • 45.
  • 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
  • 56.
  • 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
  • 63.
  • 64.
  • 65.
  • 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