Académique Documents
Professionnel Documents
Culture Documents
Cancers
Joseph M. Herman MD, MSc
Associate Professor
Johns Hopkins Department of Radiation Oncology and
Molecular Radiation Sciences
Baltimore, Maryland
March 8, 2014
Contributions
Objectives
Gastrointestinal Cancers
Esophageal
Stomach
Pancreas
Rectal
Anal
Hepatocellular
3/10/2014
Gallbladder
Bile Duct
Esophageal Cancer
Esophageal Cancer
Work-up
Endoscopic biopsy
CT chest, abdomen and pelvis
EUS for T and N staging, RT Planning
PET: 15% have occult metastatic disease
Esophageal Cancer
Treatment T1a & T1b
T1a (lamina propria or muscularis mucosa
invasion)
Very low risk of distant mets (<3%) and nodal
mets
Endoscopic mucosal resection adequate
60 Gy + 5-FU
RTOG 8501
RT vs. CRT
1
R
A
N
D
O
M
I
Z
E
Week
5
8
11
CDDP (75mg/m2)
5-FU (1000mg/m2) x4d
RT (5000cGy)
RT alone (6400cGy)
RTOG 8501
RT vs. CRT
LF (crude)
LF (2 yr)
(%)
(%)
RTOG 85-01
50
45
47
INT 0123
50
55
52
INT 0123
64
50
56
German
> 60
51
58
Esophageal Cancer
Rationale for Trimodality Therapy?
Esophageal Cancer
Who needs/will need surgery?
The German Esophageal Cancer Study Group attempted to answer this
question:
Patients:
Arm A:
CRT followed by Sx
Arm B:
Local
Control
at 2 yrs
(%)
Median
Surv
3-year
Surv (%)
Txrelated
mortality
(%)
CRT +
Surg
64
16 mo
31
13
58
18
CRT
41
15 mo
24
3.5
55
3-year
3-year
Surv: no
Surv:
chemo
chemo
response response
(%)
(%)*
p<0.05
T2-4 or N+ SCC/ACA of
Esophagus:
Surgery vs. CRT followed
by Surgery?
n = 363
T2-3N0-1
86 SQC
273 ACA
3-year
Survival
26 months
48%
41.4 Gy
CarboP Sx 49 months
paclitaxel
59%
Grade 3: n=12
Grade 4: n=0
Grade 5: n=0
Non-hematologic: n=28 (16%)
Grade 3: n=26
Grade 4: n=1
Grade 5: n=1
*No significant difference in post-operative complications
CRT + surgery
145 (92.3%)
12 (7.6%)
p<0.002
Esophageal Cancer:
Radiation Technique
Esophageal Cancer
EBRT Dose Escalation - RTOG 9405
187 SCC
31 ACA
Med S
2 yr S
LRF TR death
50.4 Gy
18 mo
40%
52%
2 pts
64.8 Gy
13 mo
31%
56%
11 pts*
Esophageal Cancer
Treatment Planning Considerations
50.4 Gy to tumor
5 cm superiorly and inferiorly, 2 cm radially
CTV: 4 cm sup/inf, 1cm radial; PTV: 0.5cm expansion with daily KV,
CBCT use to be considered for distal lesions along with planning 4DCT
Dose-limiting structures
First Course
Cone Down
Cumulative
IMRT
(N=254)
p-value
p=0.040
91
76.8%
23.2%
47
84.4%
15.6%
p=0.962
266
100
30
66.8%
25.1%
7.5%
204
72
25
67.8%
23.9%
8.3%
p=0.230
54
75
227
40
0
1
13.6%
18.9%
57.2%
10.1%
0%
0.02%
56
63
150
31
1
0
18.6%
20.9%
49.8%
10.3%
0.03%
0%
p=0.086
180
42
140
34
45.5%
10.6%
35.4%
8.6%
125
51
105
20
41.5%
16.9%
34.9%
6.6%
Overall Survival
p=0.009
MD
Anderson
Experience:
Overall
Survival
IMRT
3DCRT
Median
Survival
36 months
5-year OS
IMRT
Median
Follow-up
34.8 months
3-D
81.2 months
24 months
31.3%
42.4%
MD Anderson Experience
Conclusions
MD Anderson Experience
Conclusions
Limitations:
Retrospective
Gastric Cancer
Adjuvant Therapy in
Gastric Cancer
Only Site
Component
29%
4%
6%
88%
54%
29%
Gastric Cancer
Indications for Radiation Therapy
Post-op
Stage III
Positive margins
T2N0 with unfavorable features (LVSI and/or < D2
lymph node dissection)
Pre-op
Borderline resectable at presentation
GE junction
Unresectable
Gastric Cancer
Adjuvant Chemoradiation
Resected stage IB-IV stomach and GE junction tumors
Randomization: surgery alone or adjuvant chemo x 1 cycle, 45 Gy
+ 2 cycles 5FU and leucovorin, chemo x 1 cycle
Perioperative Chemotherapy
MAGIC trial
Resectable gastric or GE junction tumors
Randomization: surgery alone vs. ECF x 3
cycles before and after surgery
5-year overall survival: 36 v 23%
However, no increase in pathologic response
rate
S alone
ADJ Rx
5-yr survival
0116
MAGIC
26%
23%
44%
36%
Local relapse
0116
MAGIC*
19%
21%
7%
14%
XP x 6
Ib-IVa
D2
Gastric
458 pts
(2004-2008)
R
XP x 2 CRT XP x 2
All Patients
P = 0.0862
Node + Patients
P = 0.0365
ARTIST Trial
Conclusions
Chemotherapy or CRT generally well-tolerated with relatively good
treatment completion rates (~80%)
In limited trial size, trend only in DFS benefit with addition CRT
after D2 resection
Benefit in patients with positive lymph nodes on subgroup analysis
Planned ARTIST II trial to build on this subgroup
Postoperative CRT is still a standard of care
Ib-IVa
Gastric
GEJ
788 pts
R
ECC x 3 Gastrectomy CRT
+D1 surgery
Future Directions
3/10/2014
47
Gastric Cancer:
Radiation Technique
Gastric Cancer
Treatment Planning Considerations
45Gy adjuvant; 50.4-54Gy microscopic/gross disease
APPA standard; IMRT if constrained by heart/kidney
Simulate and Rx with empty stomach
Daily KV; CBCT and 4D-CT use to be considered if
unresectable/preoperative, proximal, concern with kidney constraints
and/or considering boost > 45 Gy
Dose-limiting structures
Treatment Planning
Empty Stomach
Treatment Planning
Full Stomach
R KIDNEY
LIVER
PTV
HEART
L KIDNEY
PTV
LIVER
L KIDNEY
HEART
R KIDNEY
Gastric Cancer
Treatment Planning Principles
Target: residual stomach and resected tumor bed, stump,
anastomoses, defined based on pre-operative imaging and
placement of surgical clips
Nodes: lesser and greater curvature; celiac axis including
pancreaticoduodenal; suprapancreatic, splenic, and porta
hepatis; paraesophageal/lower mediastinum for proximal
lesions
Gastric LN Contouring
Atlas; Wo et. al.; PRO
2012
Gastric Cancer
Treatment Planning Considerations
GE junction lesion
Gastric Cancer
Treatment Planning Considerations
Gastric Cancer
Treatment Planning Considerations 3-D vs IMRT
Results of comparative studies of 3-D vs IMRT have been mixed; benefit
marginal/limited to patients with kidney disease or proximal lesions due to
cardiac constraint
Pancreatic Cancer
3/10/2014
59
Outline
Pancreatic Cancer
Resectable Disease
Unresectable Disease
Borderline Resectable Disease
3/10/2014
Imaging
1. Abdominal US; if positive, then
2. Helical, contrast-enhanced,
abdominal CT; or go to CT directly
3. Chest/abdomen CT
4. PET/CT if equivocal findings
Biopsy nondiagnostic
individual decision
Repeat attempt
Laparotomy
? Consider PET/CT to find
additional candidate
lesions to biopsy
Pancreatic Cancer
Diagnosis
Laboratory tests
CBC, electrolytes, renal and
hepatic function, amylase,
lipase, PT, PTT, hemoglobin
A1c, CA 19-9
Pancreatic Cancer
Clinical Staging
1. Systemic Spread
2. Local Tumor Relationships
3. Performance status
Potentially
Resectable (20%)
Localized
Borderline
3/10/2014
Unresectable (80%)
Metastatic
Locally Advanced
Patient Unfit for
Surgery
63
Resectable PCA
Unresectable PCA
3-D CT Reconstruction
CT Angiogram
3/10/2014
67
No.
Patients
21
22
20
11
.03
60
54
16
12
.099/.165
ESPAC-1 (2001)
No chemo
146
139
20
16
.011
179
175
23
20
.005
187
201
20
17
.12
ACOSOG Z5031(2010)
89
25
537
551
24
23
.39
45
45
24
24
NS
5-FU/LV
Gem
Med.
Survival
P-Value
GITSG 9173
Treatment Schema
10-yr OS
(updated)
43 patients with
resected
pancreatic
tumors
Observation
0%
5-FU/EBRT
19%
ESPAC-1
Study Design & Results
ESPAC-1
Conclusions and Criticisms
Conclusions
Adjuvant chemotherapy has a significant survival benefit in
patients with resected pancreatic cancer, whereas adjuvant
CRT has a deleterious effect on survival
Trial Criticisms
No details or quality assurance of radiation delivery
Only 62% of pts assigned to CRT could be documented to
receive protocol therapy
Local failure 62% but no analysis of treatment effect on LR
rate only 18% had positive margins
2x2 factorial design (appropriate only if no interaction
between treatment arms)
Neoptolemos et al, NEJM 2004
Adjuvant Chemoradiation
Retrospective review, Johns Hopkins
616 patients s/p pancreaticoduodenectomy
345 observation, 271 adjuvant CRT
Survival benefit seen with adjuvant CRT
Median survival 21.2 mos vs. 14.4 mos
5-year survival 20% vs. 15%
0.80
Observation Only
0.00
0.20
Survival
0.40
0.60
Chemoradiation
mOS
2-yr OS
5-yr OS
0
CRT
21.9mo
45.5%
25.4%
1
Obs
14.3 mo
31.4%
12.2%
2
Follow-up(yrs)
Hsu et al. Ann Surg Oncol. 2010
RTOG 9704
Treatment Schema & Results
538 patients resected, randomized (451 analyzed)
Gem
5FU/CRT
Gem
5FU
5FU/CRT
5FU
Overall Survival
Regine et al, JAMA 2008; Regine et al, Ann Surg Oncol 2011
Overall
Survival
Adjustment
Variable
Comparison
Adjusted HR
(95% CI)
P
Value
Nodal
Involvement
No vs. Yes
1.62
(1.27, 2.06 )
0.0001
Gemcitabine
vs.
5-FU
1.15
(0.92, 1.43)
0.22
0.77
(0.62, 0.96)
0.02
Treatment
RT QA Score
Pancreatic Cancer
Adjuvant Chemotherapy Alone
CONKO-001
Gemcitabine vs. Observation
Improved DFS, OS (22.1 mo vs. 20.2 mo,
p=0.06)
Excluded patients with CA 19-9 >90
ESPAC-3
Gemcitabine vs. Bolus 5-FU
OS 23.6 mo vs. 23.0 mo (p=0.56)
Toxicity higher with 5-FU, QOL same
3/10/2014
77
100
Dead Total
CA19-9 <= 90 231 293
CA19-9 > 90 41 42
75
Log-rank p-value
<0.0001
50
MST = 20.0 months
25
MST = 10.4 months
0
0
Patients at Risk
CA19-9 <= 90 293
CA19-9 > 90 42
1
2
3
4
5
Years after Randomization
225
123
78
63
58
17
3
1
1
1
Berger et al.
Pancreatic Cancer
Phase III Adjuvant Therapy Trials
Patients
with
Positive
Margins
Patients Patients
with
with Node
T3/T4
Positive
Disease Disease
Local
Recurrence
Rate
Median
(mos)
3-Year
5-Year
GITSG
0%
--
28%
47%
21
24%
19%
EORTC
23%
0%
50%
51%
17.1
30%
20%
5-FU-CRT
33%
70%
65%
28%
16.9
22%
18%
GEM-CRT
35%
81%
68%
25%
20.6
31%
22.2%
CONKO
17%
86%
72%
37%
22.1
34%
22.5%
RTOG
4 cycles of Gem
R0 Resection
<8 weeks after surgery
N=90
2 cycles of Gem
Chemoradiation (50.4
Gy/Gem-300)
RTOG 0848
Treatment Schema
Adjuvant Pancreatic
Cancer:
Radiation
Techniques
3/10/2014
82
SMA
RP margin
Pancreatic Cancer
Patterns of Failure
A
Dashed 3D
Solid - IMRT
Comparison of
IMRT to 3-D
Bowel
R Kidney
Stomach
GTV
Borderline
Resectable
Pancreatic Cancer
3/10/2014
88
Pancreatic Cancer
Margin-Positive Resection
Author (Year)
Herman (2008)
Neoptolemos (2001)
Benessai (2000)
Sohn (2000)
Millikan (1999)
Nishimura (1997)
Sperti (1996)
Yeo (1995)
Willett (1993)
Margin
Med Surv
341
101
15
184
22
70
19
58
37
R1
R1
R1/2
R1/2
R1
R1/2
R1/2
R1/2
R1/2
15
11
9
12
8
6
7
10
12
SMA
CXRT
Well-vascularized
rim, hypoxic core
Positive
Surgical
Margin
Tumor
Borderline Resectable
Resection Determined by Vessel Involvement
Resectable
Borderline
Locally
Advanced
Borderline Resectable
MDACC Retrospective study Oct 1999 - Aug 2006
160 (7%) of 2,454 PCA were borderline
resectable
125 (78%) completed CXRT and restaging, 66
(41%) underwent PD
62 of these (94%) underwent a margin-negative
resection, and only 30% node positive
Borderline Resectable
Outcome of multimodality therapy (n=129)
Example
N (%)
Resected
n (%)
84 (69)
70 (83)
15 (12)
15 (100)
2 (2)
0 (0)
+6%
Stable
Disease
-38%
Partial
Response
v
v
+22%
Progressive
Disease
(Local)
Alliance A021101
Treatment Schema
Patient with
BLR PDAC
(Intergroup
Definition)
P
R
ER
E
GI
S
T
E
R
E
N
R
O
L
L
m
FOLFIRINOX
4 x 14 day
cycle
+ 2 - 6 weeks
break
R
E
S
T
A
G
E
50.4g
EBRT
+ CAPE
1 x 38 day
cycle
+ 4 10
weeks
break
R
E
S
T
A
G
E
SURGERY
+68
weeks
break
R
E
S
T
A
G
E
GEM
2 x 28
day
cycle
F
O
L
L
O
W
Locally Advanced
Pancreatic Cancer
3/10/2014
96
Induction regimen
Maintenance
chemotherapy
Median OS
FFCD/SFRO
ECOG
Gemcitabine until
progression
Gemcitabine x 5 cycles
1-year survival
ECOG 4201
(n= 71)
Gem
Gem+
RT
P-value
G3/4 Fatigue
6%
32%
0.006
G3/4 GI
14%
38%
0.03
SCALOP Trial
P=0.01
SCALOP Trial
Capecitabine
Gemcitabine
PFS- 9 months*
62.9%
51.4%
Median PFS
12.0 months
10.4 months
Median OS (p =0.01)
15.2 months
13.4 months
1 year OS
79.2%
64.2%
None
18%
Non- hematological
toxicities*
12%
26%
Treatment Results
Single-institution Studies
Single Institutional Studies - Chemoradiation
MDACC, 2006
50.4/28fx
UCSF, 2007
50.4/28fx
MSKCC, 2008
50.4/28fx
Erlotinib + Gem
18.7
MDACC, 2009
50.4/28fx
Gem/Ox/Erb then
Cape XRT Erb
19.2
U Michigan, 2012
52.5/25fx
IMRT
Gem then
Gem IMRT
14.8
50.4/28
IMRT
23.6
MDACC, 2012
Cape + Bev
Cape
14.4
17.0
FOLFIRINOX
FOLFIRINOX Gemcitabine
ORR
31.6%
9.4%
Median PFS
6.4 months
3.3 months
Median OS*
11.1 months
6.7 months
48.4%
20.6%
1 year OS
Gemcitabine
8.5 months
6.7 months
35%
22%
Progression-free
survival
5.5 months
3.7 months
6-month PFS
44%
25%
Response rate
23%
7%
3.9 months
(range, 0.1-21.9)
2.7 months
(range, 0.1-21.5)
Overall survival
One-year survival
Treatment duration
% protocol dose
- nab-paclitaxel
- Gemcitabine
80.6%
75.2%
HR 0.72
(p<0.0001)
HR 0.69
(p<0.0001)
p<0.0001
--84.6%
Von Hoff
NEJM
2013
Von Hoff, Gastrointestinal
Cancers
Symposium,
2013
Extensive
metastatic:
Smad4 loss
Limited metastatic
Iacobuzio-Donahue et al, JCO, 2009
RTOG 1201
SMAD4-Directed Treatment in LAPC
Locally advanced
pancreatic cancer
Stratify:
Smad4 Status
Ca 19-9 < 90
Gem/Abraxane x 4 cycles
50.4 Gy
Gem/Abraxane x 4 cycles
63 Gy IMRT
Gem/Abraxane x 4 cycles
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
ABC
IMRT
Image Guided
IMRT Plan
SBRT Plan
3/10/2014
112 2014
Reese et al. Sem Rad Onc
Pancreatic Cancer
Treatment Planning Considerations
50.4-54 Gy adjuvant/gross disease (conedown at
45Gy) IMRT preferred over 3-D based on published
experience
Simulate and Rx with empty stomach (adjuvant), contrast
for intact tumors
Daily KV; 4-D CT and CBCT for unresectable/borderline
resectable or localizable positive margin
Dose-limiting structures:
3/10/2014
113
3/10/2014
115
SBRT in LAPC
Phase II Multi-institutional Trial
(Johns Hopkins, Stanford, MSKCC)
(GEM, up to 1
Cycle
allowed)*
1 week
F-SBRT
6.6 Gy x 5
Mon-Fri 1 week
break
break
GEM Chemotherapy
(3 wks on, 1 wk off)
Until toxicity or
progression
Stereotactic Body
Radiotherapy
PTV
121
Toxicity
Acute GI
Grade 2: 0%
Grade 3: 12.2%
Late GI
Grade 2: 2.1%
Enteritis
Grade 3: 8.5%
Fistula (1)
Ulcer (3)
SBRT in LAPC
Summary of Trials
Study
Grade 3 Toxicity *
Acute
Late
Regimen
Median OS
Months
Local control
(1 year)
Mahadevan
(2010)
GEM
36
8-12 Gy x 3
14.3
78%
8% G3
6% G3
Polistina
(2010)
GEM
23
10 Gy x 3
10.6
50%
Lominska
(2011)
5-FU/GEM
28
4-8 Gy x 3-5
5.9
86%
7.1% G3
Chuong
(2012)
GTX
16
5-10 Gy X 5
15
81%*
5.3% G3
Tozzi
(2013)
GEM
30
8 Gy x 5
11.0
86%
Gurka
(2013)
GEM
10
5 Gy x 5
12.2
40%
Herman, (2013,
Multi-center)
49
6.6 Gy x 5
13.9
83%
12.2%
10.6%
Conclusions
Role of XRT of in BRPC and LAPC
CTX and CRT are complementary modalities
CRT most likely to help after CTX
Exclude bad biology
Standard is Gem +/- second agent, FFX
(2-4 mo) then CRT
CRT must be well-tolerated
Small fields to the gross tumor only (1-2 cm)
Evaluation of dose escalated IMRT (RTOG)
Investigation of fractionated SBRT continues (exclude
if duodenal involvement on EUS unless going to
surgery, PPI)
Pancreatic
Cancer
Treatment
Resectable
Consider
neoadjuvant CTX
+/- CRT
Pancreatectomy
(1) 6 months of CTX
(5-FU, GEM,
combination CTX)
(2) CTX followed by
5-FU or GEM-based
CRT for high-risk
features
(3) Tailor CTX or RT
based on
pathological
features,
biomarkers, family
history, patient
preference
(4) Observation
Borderline
Resectable
Unresectable/
locally advanced
Reassess for
surgery every 2-3
months during
therapy; if
resectable,
consider adjuvant
CTX
Metastatic
(1) GEM alone
(2) GEM + NP
(3) 5-FU,
leucovorin,
irinotecan, and
oxaliplatin
(FOLFIRINOX)
(4) GEM, taxatere,
and xeloda (GTX)
Palliative radiation
as needed
3/10/2014
126
Lower GI
Rectal Cancer
3/10/2014
129
Rectal Cancer
Work-up for preoperative patients
H+P
Rectal exam Location in relation to anorectal ring*, size,
tethered, circumferential, ulcerated, sphincter tone
Full Colonoscopy
Synchronous primaries in up to 5%
CT C/A/P
Liver mets
Lung mets/nodal mets also common
Rectal Cancer
Pre-operative Tumor Assessment
CT
*TRUS
MRI
Muscularis
propria
Tumor
Rectal Cancer
Commonly Considered Preoperative Strategies
Short-course RT only
5 Gy x 5 (1 week)
1 week
Surgery
Chemotherapy if
node +
4-7+
weeks
Surgery
Fluoropyrimidinebased
chemotherapy
Rectal Cancer
Surgical Options
Local excision
Distal (within 8 cm anal verge), T1-T2
No LVI, not high grade, no signet ring or colloid histology
Abdominoperineal Resection
Lower 1/3
Rectal Cancer
Surgical Options
Local excision
Distal (within 8 cm anal verge), T1-T2, <30%
circumference
no signet ring or colloid histology
Abdominoperineal Resection
Lower 1/3
Rectal Cancer
Local Excision
Transanal excision:
Criteria
<30% circumference of rectum
<3 cm in size
Margin clear (>3 mm)
Mobile, nonfixed
Within 8 cm of anal verge
T1 only
No lymphovascular (LVI) or perineural invasion
No grade 3
No evidence of lymphadenopathy on pretreatment imaging
NCCN guidelines
Rectal Cancer
Local Recurrence T2
T2: p=0.01
LE
T2
LAR/APR
22%
15%
Rectal Cancer
Role of Chemoradiation After Local Excision
Adjuvant chemoradiation is considered for:
T1 lesions with negative factors (positive margin)
All T2 lesions
ACOSOG Z6041
Study Design
Primary Objective: 3-year DFS in uT2N0
uT2
rectal
cancer
(EUSMRI)
Chemoradiation with
capecitabine (850
mg/m2 bid M-F x 5
weeks) and
oxaliplatin (50 mg/m2
IV D1, 8, 22, 29).
50.4 Gy (54 initial
cohort)
T0-T2 and
negative
margins:
Observation
Local
excision
T3 or
positive
margins:
radical
resection
F
o
l
l
o
w
<8 cm from
anal verge
<4 cm size
Garcia-Aguilar, et al, ASCO 2010
ACOSOG Z6041
Pathological Tumor Characteristics
Pathology
Overall
n = 77
Original dose
n= 52
Revised dose
n = 25
76 (99%)
1 (1%)
52 (100%)
0 (0%)
24 (96%)
1 (4%)
0.9 1.1
2
0.9 1.1
2
0.9 1
0
Tumor T stage
T0
Tis
T1
T2
T3
Tx
34 (44%)
5 (7%)
10 (13%)
23 (30%)
4 (5%)
1 (1%)
25 (48%)
3 (6%)
7 (13%)
14 (27%)
2 (4%)
1 (2%)
9 (36%)
2 (8%)
3 (12%)
9 (36%)
2 (8%)
0 (0%)
43 (56%)
34 (44%)
30 (58%)
22 (42%)
13 (52%)
12 (48%)
ACOSOG Z6041
Conclusions
Despite a high cCR rate, neoadjuvant CRT with
CAPOX led to unacceptably high toxicity for uT2N0
patients
In the original RT dose group, having at least one >
grade 3 AE resulted in delayed CRT
Completing CRT increased the likelihood of having a
cCR at LE
Consider neoadjuvant capecitabine based CRT in
select patients with low lying T2N0 lesions
Rectal Cancer
T2-T4, N+
Total mesorectal excision
(TME) standard for T2-T4
Surgery
Improved local control
(<15%)
Increase in sphincter
preservation
Radiation
Neoadjuvant >Adjuvant
Chemotherapy
5-FU + ? with RT
Neoadjuvant chemo alone
Rectal Cancer
Rates of LRF After Surgery
Overall Survival
Distant Mets
Neoadjuvant
chemoradiation
decreases rates
of local
recurrence
Local Recurrence
5-yr OS:
5-yr LR:
G 3-4 acute tox:
Long-term tox:
Full-dose RT:
Full-dose chemo:
p=0.8
p=0.006
p=0.001
p=0.01
p<0.001
p<0.001
FFCD 92-03
EORTC 22921
FFCD 92-03
No difference in
PFS, OS, or SP
NSABP R-04
Treatment Schema
T3-4, N+ Rectal CA
TME rectal surgery
ALL PRE-OP
n=1,606
Capecitabine = 825 mg/m2 PO BID
5-FU = 225 mg/m2/day CI
Oxaliplatin = 50 mg/m2 weekly x 5
End Pt: LRR
Group 2:
5-FU + oxaliplatin
+ XRT
Group 3:
CAPE + XRT
surgery
Phase III
Group 1:
5-FU + XRT
Group 4:
CAPE + oxaliplatin
+ XRT
Roh et al.Roh
ASCO
2011
et al.
ASCO 2011
NSABP R-04
Results
Presented at ASCO 2011, Abstract #3503
July 2004 August 2010, 1,609 patients enrolled
Rectal Cancer
Neoadjuvant Chemoradiation Trials
Author/Regimen
dose/fx
pCR
(%)
3+ Acute
Tx
48
48
50.4/1.8
50.4/1.8
10.0
21.0
379
368
50.4/1.8
50.4/1.8
14.0
19.0
Chau et al.
Induction CAPOX
77
50.4/1.8
24.0
Fernandez-Martos et al.
Induction CAPOX
Adjuvant CAPOX
56
52
50.4/1.8
50.4/1.8
14.0
13.0
Cardenes et al.
Induction CAPRI
18
50.4/1.8
33.0
p value
8%/24%
8%/24%
11%
25%
p=sig
7% Heme
4% GI
17%
51%
p=sig
5%/9%
Rectal Cancer
Conclusions
Rectal Cancer
Neoadjuvant Chemotherapy
Chemo/RT
Schema:
SD/PD
FOLFOX x 6
BEV x 4
PR/CR
Primary Endpoints:
3 year LR rate
3 year DFS rate
OS
TME Surgery
FOLFOX
Adj CRT if + margin
Results:
32 patients enrolled, only 2 CRT, rest TME
8 had CR (25%)
All margin-negative (R0) resections
4 year LRR=0, DFS=84%
Schrag et al. JCO 2014
PROSPECT Trial
Randomized Phase II/III
Treatment (randomized 1:1)
Stage II-III rectal cancer 5-12 cm from anal verge
Clinical T3N0, T3N1, T2N1
Selective
Neoadjuvant FOLFOX x 6 then re-evaluate
If > 20% response rate, TME + FOLFOX x 6
If response < 20%, chemoradiation followed by
TME + FOLFOX x 2
Short-Course Radiation
Therapy: Less is Better?
25 Gy in 5 Fx + TME
(897 pts)
TME Only
(908 pts)
Primary Endpoint: LR
- Powered to detect 10% vs 5% (with RT)
Kapiteijn E, et al.: NEJM 2001, 345: 638-46
S Only
P-Value
LR
2.4%
8.2%
<0.001
OS
DM
82.0%
14.8%
81.8%
16.8%
0.84
0.87
Conclusions
Local control is excellent with TME
Even with TME, neoadjuvant RT improves local control
RT does not impact survival
Study does not address impact of modern chemotherapy
Local
Recurrence
P < 0.001
Neoadjuvant RT Fractionation:
Conclusions
Non-significant trend of worse local control, particularly
for lower lying cancers, long-course CRT should
remain the standard of care
SC: Following systemic chemotherapy for M1 disease
SC: Cautionary consideration for upper rectal tumors
(> 12 cm from anal verge or 8 cm from anorectal ring)
without threatened mesorectal fascia
Rectal Cancer:
Radiation
Technique
Rectal Cancer
Treatment Planning Considerations
Simulation for RT
1. Small Bowel Contrast
2. Prone with Belly Board (OBI
preferred)
3. Full Bladder
4. Perineal/ Perianal Marker
Belly Board required, particularly in postop setting; Daily KV; CBCT for QA of
bladder filling
Rectal Cancer
Treatment Planning Considerations
45Gy to primary and presacral hollow, boost to GTV +2 cm. At
50.4Gy conedown to primary only if can meet volumetric bowel
constraints*
3-D (based on published experience); IMRT when covering inguinal
LNs due to gross involvement of anal canal
Daily KV; CBCT for QA of bladder filling
Dose-limiting structures
Small bowel: V45 < 150 cc, V30 < 300 cc;
Max < 54Gy, V50< 10%, V45 < 15%, V20< 50% for each (published)
Femoral heads: V45 < 25% volume; V50 0.5cc
Bladder: V40 < 40%; V50 0.5cc
Neoadjuvant Conformal RT
A.
B.
C.
Rectal Cancer:
Intensity-modulated
Radiation Therapy
N=61 vs. 31
RTOG 0822:
Treatment Schema
Radiation Therapy
Pelvic IMRT: 45 Gy in 25 fx
R
3D-CRT boost: 5.4 Gy in 3 fx to total dose of 50.4 Gy in 28 fx
E PLUS
G Concurrent Neoadjuvant Chemotherapy
I Capecitabine, Oxaliplatin
S (4-8 wks)
T Surgery
E (4-8 wks)
R Adjuvant Chemotherapy
FOLFOX
*Compared to RTOG 0247: Primary endpoint: reduction in combined
Grade 2+ GI acute toxicity
RTOG 0822:
IMRT Technique / Constraints
Contouring guidelines were provided for GTV,
CTV, PTV, and supplemented with a RTOG
consensus anorectal contouring atlas, which
was provided online and published for
reference.*
Planning constraints were primarily aimed at
reducing the volume of small bowel receiving
higher doses of radiation (constraints at 35Gy,
40Gy, 45Gy dose levels).
*Myerson RJ, Garofalo M, et al. IJROBP 2009,74(3):824-30. Epub 2008 Dec 29
RTOG 0822:
Contouring for 3-D/IMRT
RTOG 0822:
Results
0822
0247 (Arm 2)
35/68 (51.5%) 30/52 (57.7%)**
6.2% reduction with IMRT
p-value
0.31
NS
RTOG 0822:
Conclusions
First multi-institutional, prospective study of use of IMRT
in rectal cancer and largest phase II clinical experience
to date
Rectal IMRT was feasible with a high rate of contouring
and planning compliance, likely attributable to the
utilization of a standardized RTOG anorectal contouring
atlas
IMRT did not result in a statistically significant reduction
of acute grade 2 GI toxicity when compared with
RTOG 0247
IMRT use in rectal cancer remains to be more clearly
defined
Simulation
Prone, contrast, belly board, full bladder (9)
Anal Cancer
Anal Anatomy
Anorectal ring
- Columnar (1-2 cm)
- Between anorectal ring
and pectinate line
- Nonkeratinizing
squamous cell (2 cm)
- Below anal verge
- Keratinizing
squamous cell
Abeloff, 2008
Anal Cancer
AJCC Staging
Anal Cancer
Staging / Work-up
Routine work-up:
History and physical examination: DRE, palpation of inguinal lymph nodes
Gynecologic examination in women to rule out vaginal invasion and other
HPV-associated malignancies
Routine laboratory studies (no tumor markers)
Anoscopy, proctoscopy, colonoscopy
CT chest/abdomen/pelvis, +/- pelvic MRI
Anal Cancer:
PET/CT Imaging
UKCCCR ACT I
Prospective trial: RT vs. CRT?
United Kingdom Coordinating Committee on Cancer
Research (UKCCCR ACT I). Included anal canal and
margin cancers.
Arm A: 45 Gy
Arm B: 45 Gy + 4-day 5FU infusion during first and last weeks +
MMC only on day one of cycle 1
then BREAK
UKCCCR ACT 1
Results
Lancet 1996;348:10491054
UKCCCR ACT I
Major Findings, 13-year Update
RTOG 87-04/ECOG
Can We Do Without Mitomycin C?
Arms
5-yr LR
5-yr CFS
5-yr
DFS
5-FU/RT
145
36%
58%
50%
5-FU/
MMC/RT
146
17%
(p<0.001)
64%
(p=0.09)
67%
(p<0.003)
ACT II
Can Cisplatin Do Better than MMC?
ACT-II trial: 940 patients treated between 2001 and
2008 randomized to RT (50.4 Gy no break),5FU
(1000 mg/m2/day) days 1-4, 29-32, and either
ACT II Update:
Late Responses
29% of pts not in CR at 11 weeks achieved CR at 26
weeks
Clinical CR at 26 weeks was a better predictor of PFS
than 11 weeks
Clinical CR at 26 weeks may be a good phase II
endpoint
26 weeks, rather than 11-12 weeks, is a validated assessment
time point for anal cancer
ACT II
Conclusions and Limitations
Conclusions
95% CR and 75% recurrence free survival are higher than prior
studies, possibly related to omitting the 6-week break in
radiation
No differences in CR between MMC and CDDP or in RFS with
or without maintenance chemotherapy
RT/5FU/MMC remains the standard of care
Assessment may be done at 26 rather than 12 weeks
Limitations
Abstract presented at ASCO in 2009, updated in 2012, still no
published manuscript
Some have interpreted the study to indicate that CDDP may be
substituted for MMC, but this was powered as a superiority
study (with negative results), not as an equivalence study
R
Stratifications a
Gender
n
Clinical N
d
T size
o
m
n = 649
i
z
e
Radiation therapy 45 to 59 Gy
5-FU/Cisplatin 2 cycles
5-FU/Cisplatin 2 cycles
Radiation therapy 45 to 59 Gy
100
75
50
25
0
0
Patients at Risk
RT+5FU/MMC
RT+5FU/CDDP
325
324
FailedTotal
RT+5FU/MMC 122 325 log-rank p-value =0.006
RT+5FU/CDDP159 324 HR =1.39 (1.10, 1.76)
2
4
6
8
Years after Randomization
234
218
204
181
144
121
59
57
75
50
25
0
0
Patients at Risk
RT+5FU/MMC
RT+5FU/CDDP
325
324
FailedTotal
RT+5FU/MMC 87 325 log-rank p-value =0.026
RT+5FU/CDDP115 324 HR =1.37 (1.04, 1.81)
2
4
6
8
Years after Randomization
283
271
235
213
168
151
68
76
Anal Cancer:
Radiation
Technique
Anal Cancer
Treatment Planning Considerations
Simulation for RT
1. Small Bowel Contrast
2. Supine frog-leg preferred
VS
3. Prone with Belly Board*
(Daily OBI required)
4. Bladder Distension for
bowel displacement
5. Perineal/Perianal Marker
Consider when treating pelvis/boosting involved pelvic LN to higher doses
Anal Cancer
Historical RTOG Radiation Technique
Anal Cancer
Treatment Planning Considerations
Dose Recommendations for Chemoradiation:
Uninvolved areas
30-40 Gy
40-45 Gy
T2 (2-5 cm)
50-59 Gy
59-66 Gy.
RTOG 9811
Acute Toxicity with 2/3D technique, 5-FU, MMC
Grade 1
Grade 2
Grade 3
Grade 4
Heme
10%
23%
35%
26%
Derm
9%
35%
43%
5%
GI
GU
17%
16%
38%
19%
32%
3%
4%
1%
45 Gy to uninvolved R inguinal,
54 Gy to involved L inguinal
RTOG 0529
Dose-Painted IMRT in Anal Cancer
R
E
G
I
S
T
E
R
T2 and above
HIV pts eligible
Mitomycin-C 10 mg/m IV
bolus on days 1 & 29
IMRT
5-FU 1000 mg/m/day by
CI on days 1-4 & 29-32
with DP IMRT*
Primary endpoint reduction in combined grade 2+ GI
and GU acute toxicity compared to 9811
Planned secondary endpoints - heme, GI and GU
acute toxicity reduction
Gross Disease
Inguinal
Internal & external iliac
Mesorectal (peri-rectal and presacral)
Rectum and associated mesentary are target, not
avoidance structures
RTOG 0529
Disease Status
PTVA Dose
T2, N0
50.4 Gy 28 fx
42 Gy 28 fx
T3-4, N0
54 Gy 30 fx (t/c 59.4)
45 Gy 30 fx
N+
54 Gy 30 fx
3 possible options
1. LN > 3 cm: 54 Gy 30 fx
2. LN < 3 cm: 50.4 Gy 30 fx
3. No LN involvement: 45 Gy 30 fx
CTVC: inguinal
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Univariate Predictors of
Local-Regional Failure on 0529
Variable
Comparison
Gender
Tumor Measurements at
Largest Dimension (cm)
T Stage
4 vs. >4
N Stage
N0 vs. N+
AJCC Staging
(6th Edition)
II vs. IIIA/B
T2 vs. T3/4
HR
p-value
3.77
(1.15, 12.38)
6.13
(1.32, 28.41)
3.23
(0.95, 11.07)
3.71
(0.98, 14.02)
3.42
(0.90, 12.90)
0.029
0.021
0.062
0.053
0.070
Anal Cancer
Conclusions
Nigros original regimen of RT/5-FU/MMC remains the
standard of care, despite multiple large phase III trials
testing alternatives
Recent prospective data (ACT II) suggest a regressing
lesion may be followed for up to 6 months before
committing to biopsy and/or salvage surgery
RT techniques have improved dramatically from simple 2-D
APPA, to 3-D, to IMRT, with supportive prospective phase
II data demonstrating that improved technology results in
improved outcomes
Chemotherapy?
5-FU/MMC (9)
ACR Appropriateness Criteria
Radiation Dose
http://www.acr.org/QualitySafety/Appropriateness 54-59.4 (8)
Criteria/Oncology/Gastrointestinal
Radiation delivery
IMRT (8)
Routine post treatment biopsy for stable disease
Yes (1)
Hepatocellular
Carcinoma
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212
Hepatocellular
Carcinoma
Typically occurs in patients 50-60 y/o
Endemic in eastern Asia & central Africa, rare in US,
Europe, South America
Risk factors include primarily Hepatitis B, Hepatitis C,
and Alcoholic Cirrhosis
Secondary risk factors; hemachromatosis, type II
diabetes, Wilsons disease, aflatoxin exposure,
cryptogenic cirrhosis, and others
Hepatocellular Carcinoma
Diagnosis
Hepatocellular Carcinoma
Hepatocellular Carcinoma
Hepatocellular Carcinoma
5-Fraction SBRT Plan
Avoidance of
normal tissues is a
priority
Dose dependent
on normal tissues
Volume of
spared liver
Proximity to
luminal GI
organs
35 Gy in 5 fractions
September 2009
AFP 24
Hepatocellular Carcinoma
Toronto Phase I/II Study
Median survival
No thrombosis 20.5 mo (95% CI 12.9, 36.9)
Thrombosis
11.0 mo (95% CI 11.3, NA)
Survival by trial
Trial 1
Trial 2
Med Survival
11.1 months (95% CI 7.4-19.0)
25.5 months (95% CI 11.3, NA)
Bujold, JCO 2013
RTOG1112
Key Eligibility
Inclusion Criteria
Measureable HCC
Unsuitable for or refractory to:
Surgery
RFA
TACE
Child Pugh A
BCLC B or C
Platelets > 70 000 bil/L
INR < 1.7
Albumin 28 g/L
AST, ALT < 6xULN
Exclusion Criteria
Prior Sorafenib
Prior abdominal RT or Y-90
> 15 cm single HCC
> 20 cm sum of max diameters
> 5 discreet HCC
Extrahepatic disease > 2 cm
HCC extension to stomach
HCC extension to CBD
Thrombolytic therapy within 28
days of study entry
Bleeding within 60 days
requiring transfusion
Hepatocellular Carcinoma
Conclusions
SBRT can treat HCC safely
Advanced RT techniques, individualized RT and HCC
multi-disciplinary team needed
Toxicity least if CP A, < 10 cm, no PVT HCC
THANK YOU!
Questions?
Gallbladder Cancer
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230
Gallbladder
Anatomy &
Histology
Gallbladder Cancer
Imaging
Gallbladder Cancer
Patterns of Spread
Spread is both local and distant
Direct invasion
Due to thin wall and single muscular layer of GB
Gallbladder Cancer
Treatment
Surgery
Resectable 20-35% by cholecystectomy
Laparoscopic procedure should be
converted to radical with partial
hepatectomy if frozen section positive for
T1B or greater
Laparoscopic port incision should be resected
at the time of the radical surgery
Horgan et al. JCO 2012
Gallbladder Cancer
Treatment
T1, Stage IA: 85-100% (5-year OS)
Very few patients with this stage
T1a simple chole, T1b extended chole
235
Gallbladder Cancer
Treatment of Locally Advanced Disease
Chemotherapy
Very little data
Phase III Mitomycin C/5-FU vs. observation
Radiation
EBRT: Showed dose response (>54 Gy superior to
<54 Gy)
Kresl 2002 IJROBP 52(1): 167
IORT
Chao J Surg Onc 1991
Cholangiocarcinoma
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237
Cholangiocarcinoma
3% of all gastrointestinal malignancies worldwide
Most cases diagnosed in patients >60 years
In US and Western Europe, incidence is about 2
per 100,000
Considerable variation in incidence worldwide
Work-Up
Lu, Decision
Making in
Radiation
Oncology 2011
Intrahepatic Cholangiocarcinoma
Clinical Presentation
Intrahepatic Cholangiocarcinoma
Pathology
Adenocarcinoma
Diagnosis of exclusion
Negative: lung (TTF1), colon
(CDX2),pancreas (DPC4)
Positive: biliary epithelium (AE1/
AE3; CK7+ and CK 20-)
Intrahepatic Cholangiocarcinoma
Pre-operative Evaluation
Intrahepatic Cholangiocarcinoma
Management
Surgical resection is the standard of care
R1/R2: Re-resection, chemoradiation, ablation,
chemotherapy, transplant (?)
Unresectable
Embolization (Chemo/Radio/Bead)
Ablation
Chemoradiation/SBRT
Metastatic
Gemcitabine/Cisplatin
Palliation/supportive
Perihilar Cholangiocarcinoma:
Klatskin Tumor
At or near the junction of the right and
left hepatic ducts
Surgery is standard of care
Unresectable:
Transplant (select cases)
Chemotherapy (Gem/Cis)
Chemoradiation (5-FU/Gem)
SBRT
TACE
Distal Extrahepatic
Cholangiocarcinoma
Surgery is standard of care (Whipple)
Often treated with pancreatic cancer adjuvant
regimen
Positive margins: 5-FU-based CRT
Negative margins: 4-6 cycles of chemo then CRT
Unresectable
5-FU-based CRT with chemotherapy
Boost with EBRT, brachytherapy (HDR/LDR)
Transplant in select cases
Liver Transplantation
Hilar cholangiocarcinoma, neoadjuvant
chemoRT followed by liver transplant
Retrospective
71 pts with St I/II hilar CC
45 Gy in 1.5 BID followed by 20-30 Gy HDR
boost with concurrent 5-Fu, then Xeloda until
surgery
Re-staging to confirm localized disease
5-yr OS all patients 58%, if transplant 82%
13% recurrence rate in transplant group
Rea et al. Ann Surg 2005
Treatment Planning
Gallbladder
Cholangiocarcinoma
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247
Prospective Gallbladder/
Cholangiocarcinoma Study
ES0809 Ben-Josef (Michigan)
Phase II Adjuvant Xeloda/Gem followed
by Xeloda + RT (atlas)
Goal was to analyze survival (2-year)
based on this regimen (as well as toxicity)
Stratified survival based on R0 vs. R1
Malignancies that qualified: gallbladder,
hilar cholangiocarcinoma, and extrahepatic
cholangiocarcinoma
Gallbladder
Cancer
Extrahepatic
cholangiocarcinoma
THANK YOU!
Questions?