Transcript Developing IMRT for the treatment of anal cancer

IMRT for the Treatment of
Anal Cancer
Kristen O’Donnell, MS3
December 12, 2007
Anal Cancer: Just the Facts
Estimated new cases in the US in 2007
4,650
Estimated Deaths
690
Pathology
~80% Squamous cell carcinoma,
Other 20% adenocarcinoma or melanoma.
HPV associated, same pathogenic
serotypes as cervical cancer, 16 & 18
(Jemal et al., 2007; Hansen and Roach, 2007)
Anal Cancer: Just the Facts
Anatomy:
3-4 cm anal canal
Anal verge to
dentate line
Lymph node
drainage:
Perirectal
Internal iliac
Inguinal nodes
(Up-to-date; cancerbackup.org)
Staging
N
T
T0
Tis
T1 <2 cm
T2 >2 cm but <5 cm
T3 >5 cm
T4 invades adjacent
organs
N0
N1 perirectal
N2 unilateral
internal iliac or
inguinal
N3 perirectal and
inguinal and/or
bilateral inguinal
and/or internal iliac
M
M0
M1 distant metastases
(Hansen and Roach, 2007)
Current Standard is Definitive
Chemoradiotherapy for Anal Cancer
Radiotherapy alone vs.
Chemoradiotherapy.
45 Gy alone or w/ concomitant 5-FU and
mitomycin
UKCCCR, 1996: 585 epidermoid anal
cancer patients with any stage disease
randomized
EORTC, 1997: 110 patients with stage IIIAB anal cancer randomized
(UKCCCR, 1996; Bartelink et al., 1997)
Current Standard is Definitive
Chemoradiotherapy for Anal Cancer
UKCCCR
EORTC
Significantly decreases
local recurrence
59% 36% local failure
rate, Relative risk of 0.54
Decreases cancer related
risk of death after 3 years
39% 28% anal cancer
mortality, Relative risk
0.71
No significant overall
survival benefit after 3
years
Radiotherapy 58% and
Chemoradiotherapy 65%
No significant
difference in acute
toxicity
Diarrhea and skin
reaction most
common
Better complete
remission rates
54%80%
18% improvement in
locoregional control
32% improvement in
Colostomy-free survival
at 5 years
(EORCT, Bartelink et al., 1997)
Current Standard is Definitive
Chemoradiotherapy for Anal
Cisplatin and 5-FU chemotherapy with radiation
therapy is an alternative regimen
Provides similar locoregional control, colostomy free
survival and overall survival to 5-fu and mitomycin with
radiotherapy
Causes less toxicity
(Hung et al., 2003)
RTOG 98-11: Standard concomitant 5-FU/mitomycin
chemRT vs. Induction with 5-FU/Cisplatin then 5FU/Cisplatin + RT
Reduced hematologic toxicity
Decreased colostomy free survival
Complicated by induction treatment design
(Gunderson et al., 2006)
Anal Cancer Trial II being conducted in the UK
(Das et al., 2007)
Rates of Locoregional Recurrence
with Definitive Chemoradiotherapy
UKCCCR: 36% at 3 years
EORTC: ~32% at 5 years
M.D. Anderson: 14% at 3 years
Study of 167 patients treated with
definitive chemoRT for anal cancer.
(Das et al., 2007)
Patterns of Locoregional
Recurrence
Das et al. at M.D. Anderson found:
75% Recurred at anus or rectum
21% Presacral and/or iliac regions
5/5 had RT field start at the bottom of the SI joints
– 3/5 recurred above RT field, 1/5 marginal, 1/5 recurred
both above and within field
4% (1 patient) Inguinal recurrence
Compared to cited 8-15% risk of inguinal recurrence
in studies of patients not receiving inguinal RT.
Locoregional control benefit from RT
RT is very effective at inguinal nodes and iliac
nodes with adequate treatment coverage.
Need better local control at primary tumor site.
How will IMRT change these statistics?
(Das et al., 2007)
IMRT
Utilizes detailed beam shaping
Creates unique conformal distributions
and sharp dose gradients
Increase the ability to:
Target specific volumes
Limit normal tissue exposure
Use in the treatment of head and
neck, prostate and gynecologic
cancers.
IMRT in anal cancer
New application gaining support
Early studies show reduced toxicity
rates with comparable local control
and survival statistics.
Area of active study
Radiation Therapy Oncology Group is
currently enrolling for a phase II trial
(RTOG 0529).
IMRT Dosimetry studies
Chen et al. Conventional AP/ PA pelvic fields vs.
Conformal avoidance IMRT planning in 2 patients
Same PTV with IMRT plan assigned dose constraints for
femoral heads and external genitalia.
Comparable PTV coverage:
IMRT plan: 97-98% of PTV at 90% prescribed dose
Conventional AP/PA: 94% of PTV at 90% prescribed dose
IMRT spared femoral heads 58-59% vs. 71-72% of
prescribed dose and genitalia 55-63% vs. 78-97% with
conventional planning
(Chen et al. 2005)
IMRT Dosimetry studies
Lin and Ben-Josef Designed 9-field, noncoplanar IMRT plans for 5 patients with
anal cancer
Volumes:
GTV=anal tumor and positive nodes
CTV= GVT + inguinal and iliac nodes
PTV=CTV + 5 mm expansion
IMRT planning,
1° priority=PTV coverage
2° priority=limiting dose to organs at risk
Utilized Equivalent uniform dose for
optimization
(Lin and Ben-Josef, 2007) ASCO Abstract
IMRT Dosimetry studies
Results:
Homogenous dose coverage
95% of PTV receiving 99% of prescribed dose
Perineum
Genitalia
Small
Bowel
Bladder
Femoral
Necks
Pelvis
Sacrum
Dose
Constraint
(Gy)
36
36
50
50
45
50
50
Mean dose
with IMRT
(Gy)
13.5
±5.9
19.4
±16.1
18.9
± 8.2
28.8
± 3.2
15.9
± 2.3
15.9
± 1.3
24.8
± 2.4
IMRT to treat anal cancer should decrease
toxicity and has potential to improve local
control.
(Lin and Ben-Josef, 2007) ASCO Abstract
Clinical use of IMRT for anal
cancer
Single institution study of 17 anal cancer
patients treated with definitive chemoRT
using IMRT planning.
Comparative dosimetric analysis of 7 patients:
IMRT planning vs. 3-D AP/PA planning
Significant reduction in small bowel, bladder and
perineum doses
Toxicity
All patients had mild-mod dermatitis
No treatment breaks due to GI or skin toxicity
All GI and bladder toxicities were ≤ grade 2.
– EORTC trial showed frequent grade 3 GI and skin
toxicity
Hematologic toxicity unchangedslightly worse than
rate in RTOG trial
(Milano et al., 2005; Bartelink et al., 1997)
Clinical use of IMRT for anal
cancer
Single institution study of 17 anal
cancer patients treated with definitive
chemoRT using IMRT planning
Similar outcomes to standard treatment
14/17 complete response
2 year progression free survival 65%
Overall survival 91%
Colostomy free survival 82%
Local control 82%
Distant control 74%
(Milano et al., 2005)
Multicenter experience with IMRT
for anal cancer
53 patients treated at three academic medical
centers with IMRT and chemotherapy for
definitive treatment of anal cancer.
Toxicity
58% completed treatment without interruption
Improved GI toxicity rates and severity
Grade 3 in 15% with no Grade 4
RTOG 98-11: 34% of patients had Grade 3 - 4
Dermatologic, Grade 3 in 38%
Similar to studies with 2-wk treatment breaks
Better than the 48% in RTOG 98-11
Hematologic toxicities were severe and common
Grade 3 and 4 in 58% of patients as worst
Similar to RTOG 98-11 rates of 60%
(Salama et al., 2007)
Multicenter experience with IMRT
for anal cancer
53 patients treated at three academic
medical centers with IMRT and
chemotherapy for definitive treatment of
anal cancer.
Response
Complete response in 92%
Local recurrence rate 13% @ 18 months
18-month colostomy free survival 83.7%
18-month distant recurrence free
survival 92.3%
(Salama et al., 2007)
Summary
Dosimetric studies and small clinical trials
have shown reduced dosing and toxicity to
normal structures with the use of IMRT.
No decreases in treatment effectiveness or
local control rates have been detected.
Limited sample sizes and duration of
follow-up minimize the ability to detect
small variations in local control rates.
Future Studies using IMRT for
Anal Cancer
RTOG 0529
A Phase II Evaluation of Dose-Painted IMRT in
Combination with 5-Fluorouracil and MitomycinC for Reduction of Acute Morbidity in
Carcinoma of the Anal Canal.
59 patients with histologically-proven, invasive
primary squamous, basaloid, or cloacogenic
carcinoma of the anal canal; Stage 2-4 and N0N3 stage.
Currently enrolling