Gastric Cancer11

The Management of Gastrointestinal
Cancers
Joseph M. Herman MD, MSc
Associate Professor
Johns Hopkins Department of Radiation Oncology and
Molecular Radiation Sciences
Baltimore, Maryland
ASTRO Spring Refresher Course
March 8, 2014
Contributions
Thanks to the following contributors:

Christopher Crane/Matt Katz, MD Anderson
Rachit Kumar, Johns Hopkins
Kevin Stephens, Cleveland Clinic
Anusha Kalbasi and Edgar Ben-Josef, UPENN
Avani Dholakia, Johns Hopkins
William Small, Loyola University
Lisa Kachnic, Boston Medical Center
William Regine, University of Maryland
Laura Dawson, Princess Margret Hospital
Objectives
Review standard of care approaches for

each Gastrointestinal malignancy
Overview of modern clinical trials
Introduction to innovative technologies
and approaches
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
T1b (invades submucosa)

- Standard of care is esophagectomy
- Non-surgical candidate:
-
45-50 Gy + 2 drug chemo
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)
Patients: non-metastatic SCCa or ACa

CRT
30Gy/15fxn from SCLV to GE jxn initially, then 20Gy/10fxn to tumor + 5cm sup/inf
Primary Endpoint: Survival

Cooper, JAMA, 281: 1623-1627, 1999
RTOG 8501
RT vs. CRT
Herskovic, NEJM, 326: 1393-1393, 1992

Cooper, JAMA, 281: 1623-1627, 1999
Non-Operable Esophageal Cancer

Randomized Phase III Trials
Dose (Gy)
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?
Given the high rates of local failures,

adding surgery would seem like a
reasonable addition to CRT
Esophageal Cancer
Who needs/will need surgery?
The German Esophageal Cancer Study Group attempted to answer this
question:
Patients:
Only SCCa of upper and

mid- third of esophagus
Only T3-4, N0-1, M0
All pts received induction
chemo (5-FU,LV,etop, cisplatin)
Arm A:
CRT followed by Sx
Arm B:
CRT (higher dose RT)
This study was designed to be a test of equivalence.

Stahl, JCO, 23: 2310-2317, 2005
German Esophageal Trial

CRT + S vs. CRT Only
Tx
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
*In non-responders who attained a complete R0 resection, 3-yr OS increased to

32%; raises the possibility of limiting surgery as a form of salvage therapy
Stahl, JCO 2005; similar results seen in other phase III trials Bedenne, JCO 2007
T2-4 or N+ SCC/ACA of
Esophagus:
Surgery vs. CRT followed
by Surgery?
CROSS Phase III Trial

Neoadjuvant CRT vs. Sx alone
Median
Survival
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%
Hagen, NEJM 366; 22, 2012

Toxicity of treatment (CRT)
Major toxicities (Grade 3-5 CTC 3.0)*
Hematologic: n=12 (6.8%)
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

Resection rate, resection margins & pCR
Resection rate of all randomized patients:
Surgery alone
CRT + surgery
162/188 (86%)
157/175 (90%)
Resection margins:
Surgery alone
R0
110 (67%)
R1
52 (33%)
CRT + surgery
145 (92.3%)
12 (7.6%)
p<0.002
Pathologic complete response rate: 29%
Cross Phase III Trial

Conclusions
Neoadjuvant CRT with carboplatin and paclitaxel
improves survival compared to surgery alone
No increase in postoperative complications or
postoperative mortality with preoperative CRT
Low pulmonary toxicity 41.4 Gy enough??
Stage IV Esophageal Cancer

Dysphagia Palliation
RT/CRT is preferred over stent alone

70-90% dysphagia relief (median time ~ 2
wks from start of Rx)
50-70% dysphagia-free until death
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*
Minsky, JCO 20:1167, 2002
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
Spinal cord max 45 Gy

Lung*: V20 < 30%,V10 < 40%, V5 < 60%
Heart*: V40 < 30%, V25 < 50%
Liver: mean < 25 Gy, V30 < 60%
Kidney: combined mean < 18 Gy
Classic 3-D Technique
First Course
Cone Down
Cumulative
Long-term Outcomes Comparing 3-D to IMRT with

Concurrent Chemotherapy for the Treatment of
Esophageal Cancer: The MD Anderson Experience
Lin et. al., IJROBP 2012
MD Anderson Experience: Acute Toxicity

3DCRT
(N=302)
Weight Loss (% Body Weight)
10%
>10%
Feeding Tube Placement
None
Before RT
During/After RT
Esophagitis (Grade)
0
1
2
3
4
5
Nausea (Grade)
0
1
2
3
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%
Trimodality vs CRT alone pts evenly distributed [~50:50]
Overall Survival
p=0.009
MD
Anderson
Experience:
Overall
Survival
IMRT
3DCRT
Years after diagnosis
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
Acute toxicities were nearly equivalent between

3D and IMRT
There were no differences in disease specific

outcomes (LR, DM, or CSS)
IMRT was associated with longer overall survival

compared to 3D
3D had increased cardiac and undocumented

deaths
MD Anderson Experience
Conclusions
Normal tissue sparing by IMRT may reduce late

complications and non-cancer mortality
Limitations:
Retrospective
Different treatment eras
A number of patients with unknown causes

of death
Gastric Cancer
Adjuvant Therapy in
Gastric Cancer
University of Minnesota Reoperation Series: Patterns of Failure

107 patients with gastric cancer
68 patients 2nd look laparotomy
39 patients symptomatic 2nd look
Pattern
LRF
PS*
DM
Only Site
Component
29%
4%
6%
88%
54%
29%
*PS = Peritoneal spread

Gunderson, IJROBP 8:1-11, 1982
University of Minnesota Reoperation Series: Patterns of Failure
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
Median survival: 35 v 26 months

DFS: 30 v 19 months
3-year OS: 50 v 41%
Criticism: most common LN dissection was D0
Macdonald et al., NEJM 2001
SWOG-Directed Intergroup Study

0116: 10-year update
Adjuvant CRT cohort benefit:
Overall Survival- HR =1.32 (95% CI, 1.10 to
1.60; p=0.0046)
Relapse- Free Survival- HR =1.51 (95% CI, 1.25
to 1.83; p<0.001)
Second malignancies 21 pts (vs. 8 in the
control group), however this was not
statistically significant, p=0.21
Smalley JCO 2012
Update: SWOG-Directed Intergroup Study 0116
(A) Overall survival (B) Relapse-free survival
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
Cunningham, NEJM 2006
Gastric Cancer Adjuvant Therapy

MAGIC and 0116
S alone
ADJ Rx
5-yr survival
0116
MAGIC
26%
23%
44%
36%
Local relapse
0116
MAGIC*
19%
21%
7%
14%
*24% of patients who died had LR prior to death
Gastric Adjuvant Therapy

ARTIST trial
XP x 6
Ib-IVa
D2
Gastric
458 pts
(2004-2008)
R
XP x 2 CRT XP x 2
XP: Capecitabine 1000 mg/m2 bid, CDDP 60 mg/m2

CRT: 45 Gy in 25 fractions + capecitabine 825 mg/m2 bid
Primary endpoint: DFS
Lee et. al., JCO 2011
All Patients
P = 0.0862
Lee, JCO 30:268-273, 2012
Node + Patients
P = 0.0365
Lee, JCO 30:268-273, 2012
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
Gastric Adjuvant Therapy

CRITICS Trial
Ib-IVa
Gastric
GEJ
788 pts
ECC x 3 Gastrectomy ECC x 3

+D1 surgery
R
ECC x 3 Gastrectomy CRT
+D1 surgery
ECC: Epirubicin 50mg/m2, CDDP 60 mg/m2, capecitabine

1000 mg/m2 bid
CRT: 45 Gy in 25 fractions + capecitabine 575 mg/m2 bid
Dutch Trial; ~two-thirds accrual is completed
Future Directions
S-1 Japanese trial

Role of IMRT
Patient selection
Performance status
HER2 status (7-22%), RT sensitivity
3/10/2014
47
Gastric Cancer:
Radiation Technique
Gastric Cancer
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

Lung: V20 < 30%,V10 < 40%, V5 < 60%,
Heart: V40 < 30%, V25 < 50%
Kidney: combined mean < 18 Gy
Small bowel: V45 < 150 cc, V30 < 300 cc
Treatment Planning
Empty Stomach
Treatment Planning
Full Stomach
Mahmood et. al.;

PRO 2012
Dose Volume Histogram

Full Stomach
R KIDNEY
LIVER
PTV
HEART
L KIDNEY
Compliments Bill Regine

Empty Stomach
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 LN Contouring
Atlas; Wo et. al.; PRO
2012
Gastric Cancer
GE junction lesion
Gastric Adjuvant RT Consensus Report; Smalley et. al.; IJROBP 2002
Gastric Antrum lesion
Gastric Cancer
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
Pancreatic Cancer (PCA)

In the United States
40,000 new cases a year

8000 will be potentially curable
Only 1600 (~ 4%) will be alive at 5 years
Why does PCA have a poor prognosis?
3/10/2014
Anatomy: proximity to critical vessels (margin)

Biology: early metastatic spread (nodes)
Physiology: exocrine insufficiency, cachexia
Poor tolerance to treatment

Treatment resistance
Lack of adherence to evidence based approaches
61
Clinical suspicion of pancreatic tumor based on jaundice, abdominal pain,

nausea, and weight loss.
Physical examination otherwise not revealing.
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
Diagnostic and other interventions

(based on clinical factors/need)
ERCP with biopsy, biliary stenting
US- or CT-guided biopsy
EUS with biopsy of pancreatic or
nodal mass
Endoscopy with duodenal stenting
1. Biopsy/cytology positive for adenocarcinoma:

Pancreatic tumorconsider IHC or sequencing to further
define treatment options
Other tumor (duodenum, ampulla, bile duct)
2. Biopsy positive for other histology (sarcoma, lymphoma,
malignancy metastatic to pancreas): individualized therapy;
different algorithm
Multidisciplinary review and consideration

of enrollment onto clinical trial
Poor performance status:

Consider palliative
management, best
supportive care, pancreatic
enzyme supplementation
Good performance status:

Follow the treatment
algorithm presented at the
end of this presentation
(based on resectability)
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
Pancreas: Adjuvant Therapy
3/10/2014
67
Pancreatic Cancer Adjuvant Trials

Author
No.
Patients
GITSG (1985) 5-FU/XRT

Surgery alone
21
22
20
11
.03
EORTC (1999/2007) 5-FU/XRT

Surgery alone
60
54
16
12
.099/.165
ESPAC-1 (2001)
No chemo
146
139
20
16
.011
179
175
23
20
.005
RTOG (2010) 5-FU/XRT

Gem vs 5-FU
187
201
20
17
.12
ACOSOG Z5031(2010)
89
25
ESPAC-3 (JAMA 2010)

Gem vs 5-FU/LV
537
551
24
23
.39
EORTC (JCO 2010)

*Gem vs Gem/GemXRT
45
45
24
24
NS
5-FU/LV
CONKO (2008 ASCO)

Surgery alone
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%
GITSG, Kalser et al, Arch Surg, 1985
ESPAC-1
Study Design & Results
Neoptolemos et al, NEJM 2004
17.9 m vs 15.9 m (p=0.05)
20.1 m vs 15.5 m (p=0.009)
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%
No benefit for N0 patients
Herman et al, JCO 2008
Matched-Pair Analysis: Survival After Pancreaticoduodenectomy

1.00
Observation versus Adjuvant Chemoradiation, n=496
Adjuvant Therapy, p<0.001
0.80
Observation Only
0.00
0.20
Survival
0.40
0.60
Chemoradiation
Adj CRT RR: 0.59 (0.48 0.72)
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
Multivariate Analysis: Impact of Nodal

Involvement, Treatment, And RT QA
Score On Survival
All Eligible Patients (n = 416)
Endpoint
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
< Per Protocol

vs.
Per Protocol
0.77
(0.62, 0.96)
0.02
Treatment
RT QA Score
*Abrams, Regine et. el. IJROBP 2011
RTOG 9704 / US Intergroup Phase

III Adjuvant Study
*Abrams, Regine et. el. IJROBP 2011
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
RTOG 9704: Overall Survival: All Head Tumor

Location Patients
CA19-9 Level 90, CA19-9 Level > 90 (n=335)
Overall Survival (%)
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)
OS -24 mos for both arms

DFS median 11 mos (C) vs 12 mos (CRT)
Grade 4 toxicity 0% (C) vs 4.7% (CRT)
First local recurrence significantly decreased in
CRT arm: 11% vs. 24%
Van Laethem et al. JCO 2010
RTOG 0848
Treatment Schema
Adjuvant Pancreatic
Cancer:
Radiation
Techniques
3/10/2014
82
Retroperitoneal (Uncinate, SMA)

Margin
SMV
SMA
RP margin
Pancreatic Cancer
Patterns of Failure
A
Anterior-posterior (top) and lateral (bottom) views of local recurrence plots

for (A) NA (orange), (B) CA (red), (C) CRT (green), and( D) all groups. Celiac
artery (yellow) and SMA (blue) are contoured.
Dholakia et al. IJROBP 2013
Goodman et al. IJROBP 2012
Dashed 3D
Solid - IMRT
Comparison of
IMRT to 3-D
Bowel
R Kidney
Stomach
GTV
Adjuvant Therapy in Resected PCA

Conclusions
Adjuvant gemcitabine or 5-FU/LV improves OS
Adjuvant CRT is controversial
Evaluated in RTOG 0848
Pancreas task force consensus is 4-6

months of CTX, then consideration of CRT
Trials combining aggressive chemotherapy with
a short course of RT or dose escalated IMRT
should improve outcomes
Biomarkers are needed
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
Potential Effect of Preoperative

Chemoradiation
SMV
SMA
CXRT
Well-vascularized
rim, hypoxic core
Positive
Surgical
Margin
Tumor
Outline of Tumor Mass on CT

Slide courtesy of Jason Fleming, MD
Borderline Resectable
Resection Determined by Vessel Involvement
Resectable
Borderline
Locally
Advanced
Katz et al. ASO 2013
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
Median OS was 40 mo for the 66 patients who

completed all therapy and 13 mo for the 94
patients who did not undergo
pancreatectomy (p < 0.001)
Katz et al, J Am Coll Surg. May 2008
Outcome of multimodality therapy (n=129)
Median OS 33 vs.12 months, p <0.001
RECIST of 122 patients restaged following neoadjuvant therapy

RECIST
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)
21 (17%) progressive disease due to metastases, 0 resected
Katz, Cancer 2012
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
Pre-enrollment phase with centralized radiographic review of staging
Centralized review of restaging studies and use of objective response metrics
Standardized indications for operation
Protocol-mandated operative procedures / vascular resection
Analysis and reporting of survival rates
F
O
L
L
O
W
Locally Advanced
Pancreatic Cancer
3/10/2014
96
Locally Advanced PCA: What We

Know and What We Still Dont Know
Outcomes are different from those with metastatic
disease and should be studied in separate clinical trials,
or stratified within a given study (NCI consensus report,
2009)
Outstanding questions:
- Does standard chemoradiation improve outcome?
- If so, how should it be sequenced relative to
chemotherapy?
- What is the best option for chemotherapy?
- How do we distinguish between truly unresectable and
borderline resectable patients?
- Patient selection? Role of stereotactic body RT?
Comparison: Phase III Studies FFCD-SFRO vs. ECOG

4201 (Modern Randomized Studies of LAPC)
Chauffert, Ann Oncol 2008
Loehrer, J Clin Oncol 2011
Induction regimen
Maintenance
chemotherapy
Median OS
FFCD/SFRO
ECOG
Cisplatin/5-FU + 6000 cGy

XRT (6 weeks)
Gemcitabine + 5040 cGy

XRT (6 weeks)
Gemcitabine until
progression
Gemcitabine x 5 cycles
8.6 vs. 13.9 months, in

favor of chemo alone
11.0 vs. 9.2 months, in

favor of induction
chemoXRT
32% vs. 53%
50% vs. 32%
1-year survival
Did ECOG study use a more

effective radio-sensitizing regimen?
Was the induction regimen
prescribed by FFCD/SFRO overly
intensive delayed administration
and total amount of subsequent
systemic therapy?
ECOG 4201
(n= 71)
Gem
Gem+
RT
P-value
G3/4 Fatigue
6%
32%
0.006
G3/4 GI
14%
38%
0.03
Retrospective Analysis of LAPC

in GERCOR Studies
Huguet, J Clin Oncol 2007
Median PFS 10.8 vs. 7.4

mos (p=0.005)
Median OS 15.0 vs. 11.7

mos (p=0.0009)
Copyright American Society of Clinical Oncology
Huguet, J Clin Oncol 2007
SCALOP Trial: Gemcitabine vs.

capecitabine-based CRT for LAPC
Histologically proven LAPC (tumor diameter 7
cm)
After 12 weeks of induction CTX* (gemcitabine +
capecitabine)
Patients w/stable/responding disease**,
subsequent CTX cycle* randomized (1:1) to
Gem (300 mg/m2) or Cap (840 mg/BID) in
combination with radiation (50.4 Gy in 28
fractions)
Primary endpoint- 9-month progression-free
survival
Mukherjee et al. Lancet Onc 2013
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%
Grade 3/4 hematological

toxicities (p =0.08)
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
Cape + Bev + Erlotinib
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
*HR 0.57, p<0.0001.

Median f/u = 26.6 months
Comparison to Gem/Abraxane
Conroy, N Eng J Med 2011
But is FOLFIRINOX tolerable?

Safety and toxicity
Conroy, N Eng J Med 2011
Phase III MPACT Trial:

Gemcitabine plus nab-paclitaxel
Gemcitabine/
nab-paclitaxel
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
Local Treatment Intensification

Locally Advanced Pancreatic Cancer
WHO benefits from RT?

Dose escalation of RT
Improved tolerability of RT allows for better
integration with aggressive systemic therapy
Patient selection
30% Die of local only disease (JHU Autopsy Series)
Iacobuzio-Donahue et al, JCO, 2009

Crane et al, JCO, 2011
JHU Rapid Autopsy Series

Local only:
Smad4 intact
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
63 Gy IMRT
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
Evolution of Radiation Therapy

Delivery
3-D RT
ABC
IMRT
Image Guided
IMRT Plan
SBRT Plan
IMRT Pancreas Cancer
3/10/2014
112 2014
Reese et al. Sem Rad Onc
Pancreatic Cancer
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:

Kidney: combined mean < 18
Small bowel/Stomach: V45 < 150 cc, V30 < 300 cc; V50<
10%, V45 < 15%, V20 < 50% and max < 54 Gy for each
3/10/2014
113
Dose Constraints for >G2

Bleeding: V55<1cc, 60Gy pt dose
Kelly et al. IJROBP 2013 Mar 1;85(3):e143-9
Stereotactic Body Radiation

Therapy?
3/10/2014
115
Potential Benefits of SBRT vs.

Standard CRT
Treat tumor + 2-3 mm
Achieve sharper dose fall-off gradients to
normal tissue
Radiobiology more favorable?
Less toxicity, short course (<1 week)
Can be combined with other modalities
Quality of life
Locally Advanced Pancreatic Cancer

Stereotactic Body Radiation Therapy (SBRT)
Standard dose chemoradiation (50.4 Gy) is unlikely to
control most unresectable pancreatic tumors
SBRT results in excellent local control and minimal toxicity
in lung cancer and other malignancies
Stanford reports of single fraction SBRT (25 Gy x 1),
resulted in excellent local control (81-100%), but high rates
of late GI toxicity (~44%)
Recently, single institution studies of fractionated SBRT
show less toxicity with similar local control and survival as
conventional CRT
Koong AC et al. Int J Radiat Oncol Biol Phys 2004;58:1017-21.

Koong AC et al. Int J Radiat Oncol Biol Phys 2005;63:320-3.
Schellenberg D et al. Int J Radiat Oncol Biol Phys 2008;72:678-86.
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
Primary endpoint: Late GI Toxicity > 4 months

Secondary endpoints: Tumor Progression Free
Survival, pre-tx biopsy, PET/CT, QOL, biomarkers
IGSBRT Daily Workflow
Stereotactic Body
Radiotherapy
Treatment Plan (6.6 Gy x 5 days)
Plan Quality Assessment
PTV
Checks plan against protocol values

For each objective, highlights those
outside of specification
Quickly allows for assessment of
protocol during treatment planning and
plan evaluation
Phase II Multi-Institutional Trial

Overall Survival
Median: 13.9 months

(range 10.2-17.9)
121
Phase II Multi-institutional Trial

SBRT Toxicity and QOL (n=49)
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)
Quality of Life (EORTC)

Mean global QOL
Scores unchanged
pre/post SBRT
Pancreas specific QOL

Improved (p<0.05)
Pancreatic pain
Body image
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)
Newly diagnosed adenocarcinoma of the

pancreas confirmed histologically
Pancreatic
Cancer
Staging evaluation including multidisciplinary

review (see table on diagnostic algorithm)
Assess resectability with
imaging, laparoscopy
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
(1) 2-6 cycles of

GEM, 5-FU, or
combination CTX
(2) 2-4 months of
CTX followed by
CRT or SBRT
(1) 2-6 cycles of

GEM, 5-FU, or
combination CTX
(2) Consider CRT or
SBRT for
consolidation
(3) Palliative
measures including
bile duct and/or
duodenal stenting
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
Follow-up for all patients will be according to the National Comprehensive

Cancer Network guidelines. In general, consider a clinical trial, pancreatic
enzyme supplementation, and/or proton pump inhibition.
Stomach and Small Bowel

Toxicity
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
CEA, Male PSA, Female Gyn exam if high risk, Preg

Assessment of bowel function low lying lesions
consider temp diverting colostomy (AVOID STENTS)
*Decision of ability to undergo sphincter preservation
should be decided pre-treatment in most all cases
Rectal Cancer
Pre-operative Tumor Assessment
CT
*TRUS
MRI
Muscularis
propria
Tumor
65-75% accuracy in tumor staging; 80-95% accuracy in tumor staging;

55-65% accuracy in mesorectal LN 70-75% accuracy in mesorectal LN
staging
staging
ROLE OF PET CONTROVERSIAL
75-85% accuracy in tumor staging;

60-65% accuracy in mesorectal LN
staging
AJCC Staging of Rectal

Cancer
Rectal Cancer
Commonly Considered Preoperative Strategies
Short-course RT only
5 Gy x 5 (1 week)
1 week
Surgery
Chemotherapy if
node +
Full course CRT

45-50.4 Gy x 1.8
Gy/fx (5+ weeks)
with 5-FU-based
chemo
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
Low Anterior Resection

Upper and middle 1/3, from 8-16 cm from anal verge
Abdominoperineal Resection
Lower 1/3
Total mesorectal excision

Improves lateral and circumferential margins
Rectal Cancer
Surgical Options
Local excision
Distal (within 8 cm anal verge), T1-T2, <30%
circumference
no signet ring or colloid histology
Low Anterior Resection

Upper and middle 1/3, >5-6 cm from anal verge
Abdominoperineal Resection
Lower 1/3

Improves lateral and circumferential margins
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
National Cancer Database (NCDB) Local

Excision Project
Trends analysis (35,179 patients)

1989 to 2003
Rectal Cancer
Local Recurrence T2
Standard of care is LAR/APR
T2: p=0.01
LE
T2
LAR/APR
22%
15%
You et al. Ann Surg 245(5):726-33, 2007
Rectal Cancer
Role of Chemoradiation After Local Excision
Adjuvant chemoradiation is considered for:
T1 lesions with negative factors (positive margin)
All T2 lesions
What is the role for neoadjuvant CRT in 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
Resected tumor margins free of tumor

Yes
No
76 (99%)
1 (1%)
52 (100%)
0 (0%)
24 (96%)
1 (4%)
Pathologic tumor size, cm *

missing
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%)
Clinical Complete Response

Yes
No
43 (56%)
34 (44%)
30 (58%)
22 (42%)
13 (52%)
12 (48%)
* Mean standard deviation is shown.

This patient was not a T0 because the presence of residual cancer cells was reported.
Garcia-Aguilar, et al, ASCO 2010
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+
(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
Inferior survival: low tumors, signet

ring/mucinous cell, Path
CRM 2 mm, T4, no pathologic CR
Rectal Cancer
Rates of LRF After Surgery
LR rates: rectal CA > CRC

Stage I: 5-15%
Stage II: 20-30%
Stage III: 20-50%
Anatomic restrictions, eg. narrow bony pelvic
field
Technical difficulty in obtaining clear resection
margins
T4 disease increases risk by a factor of 1.5-2
German Phase III Trial:

Neoadjuvant vs. Adjuvant CRT
823 patients with T3, T4 or N+ disease
1994-2002
Neoadjuvant:
5040 cGy with 5-FU continuous infusion during weeks
1 and 5, then surgery in 6 weeks
4 cycles of 5-FU given starting 1 month post-op
All patients had TME

Adjuvant:
5040 cGy plus 540 cGy boost to tumor bed, same
chemo
4 cycles of 5-FU given starting 1 month after CRT
Sauer et al, NEJM, 2004; 351: 1731-40
Overall Survival
Distant Mets
Neoadjuvant
chemoradiation
decreases rates
of local
recurrence
Local Recurrence
Sauer et al, NEJM, 2004; 351: 1731-40

Neoadjuvant vs. Adjuvant CRT
5-yr OS:
5-yr LR:
G 3-4 acute tox:
Long-term tox:
Full-dose RT:
Full-dose chemo:
76% vs. 74%

6% vs. 13%
27% vs. 40%
14% vs. 24%
92% vs. 54%
89% vs. 50%
p=0.8
p=0.006
p=0.001
p=0.01
p<0.001
p<0.001
Sauer et al, NEJM, 2004; 351: 1731-40

Type of Surgery
Greater rate of sphincter preservation in group

pre-operatively felt to need APR
EORTC 22921 and FFCD 92-03

Treatment Schema
FFCD 92-03
Gerard et al, JCO 2006 Oct 1;24(28):4620-5

Bosset et al, NEJM 2006 Sept 14;24(28):4620-5
EORTC 22921
FFCD 92-03
No difference in
PFS, OS, or SP
Gerard et al, JCO 2006 Oct 1;24(28):4620-5

Bosset et al, NEJM 2006 Sept 14;24(28):4620-5
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
Roh et al. ASCO 2011
Rectal Cancer
Neoadjuvant Chemoradiation Trials
Author/Regimen
Wong et al. (RTOG)

CAPRI
CAPOX
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
Gerard et al. (Accord)

CAP
CAPOX
p value
8%/24%
8%/24%
11%
25%
p=sig
7% Heme
4% GI
17%
51%
p=sig
5%/9%
Adapted from Minsky et al. 2010
Rectal Cancer
Conclusions
Neoadj CRT > Adj CRT

Neoadj CRT > Neoadj RT
Neoadj CI 5FU = Neoadj oral 5-FU
Neoadj 5-FU + Oxali =Neoadj 5-FU
Neoadj chemo followed by CRT ??
What about Neoadj chemo with NO RT?
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
Preoperative combined-modality chemoradiation

Chemoradiation + TME + FOLFOX x 8
PROSPECT = Preoperative Radiation Or Selective Preoperative
radiation and Evaluation before Chemotherapy and TME.
Short-Course Radiation
Therapy: Less is Better?
Swedish Rectal Cancer Trial:

Short-course Radiation
1168 patients <80, clinically resectable

1987-1990
Neoadjuvant RT-S vs. Surgery
25 Gy in 5 fractions, 3 or 4 field technique
Median follow-up: 5 years
Local recurrence 11% vs. 27% p<0.001
Overall survival 58% vs. 48% p=0.004
DSS @ 9 yrs 74% vs. 65% p=0.002
Post-operative mortality not different
Long term update, increased risk of SBO
* Non TME surgery
N Engl J Med. 1997 Apr 3;336(14):980-7.
Dutch Rectal Trial:

Does Neoadjuvant RT improve upon TME?
Operable Rectal Cancer
(1805 pts)
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
Dutch Rectal Trial: Results

2-year Median Follow-up
RTS
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
5.6% vs 10.9% at 5 -years

Peeters K, et al.: Ann Surg 2007, 246: 693-701

Peeters K, et al.: Ann Surg 2007, 246: 693-701
TROG Randomized Trial

Short-course vs. long-course CRT
Short-course 5 Gy x 5 fractions
CRT: 50.4 Gy with CI 5-FU (225 mg/m2)
Primary endpoint local recurrence

Powered to detect 15% vs 5%
Had to be MRI or TRUS T3 Nx

All patients received 4 cycles of 5-FU-based
chemo
326 patients, median follow-up 5.4 years
Ngan S, et al. J Clin Oncol 30:3827-3833, 2012
TROG Randomized Trial:

Local Recurrence
Showed trend for inferior local control for SC;

strong trend for distal tumors: 12.5% vs. 0%
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
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
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
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
*When surgeons experience with these cases is limited, or when APR

planned, consider limiting max dose to 50.4Gy
Neoadjuvant Conformal RT
A.
B.
C.
Standard three field radiation plan
PA R/L common iliacs:

Common iliacs int / ext iliacs:
Covered only if invasion of surrounding GU/GYN organs
Rectal Cancer:
Intensity-modulated
Radiation Therapy
N=61 vs. 31
Samueljan et al. IJROBP 20011
RTOG 0822: A phase II evaluation of

preoperative chemoradiotherapy (CRT)
utilizing IMRT in combination with
capecitabine (C) and oxaliplatin (O) for
patients with locally advanced rectal cancer
Michael C. Garofalo, M.D.
University of Maryland School of Medicine, Baltimore, MD
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
The anorectal RTOG atlas should be used to contour elective volumes:

http://www.rtog.org/LinkClick.aspx?fileticket=DgflROvKQ6w%3d&tabid=231
RTOG 0822:
Results
Primary Endpoint Analysis

Grade 2+ GI
0822
0247 (Arm 2)
35/68 (51.5%) 30/52 (57.7%)**
6.2% reduction with IMRT
p-value
0.31
NS
Garofalo et. al.; ASTRO 2011
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
60-year-old woman with circumferential lesion with caudal

extent 6 cm from anal verge. EUS: T3N0M0. Karnofsky
performance score (KPS) 80
Neoadjvuant Chemotherapy or CRT?

5-FU/RT (9), Chemo alone (N/A)
Radiation Dose
Appropriateness Criteria
50.4 (9), 59.4 (2), 25 Gy (1) ACR
http://www.acr.org/QualitySafety/Appropriateness Radiation delivery
Criteria/Oncology/Gastrointestinal
Conformal RT (9), IMRT (6)
Simulation
Prone, contrast, belly board, full bladder (9)
Anal Cancer
Anal Anatomy
Anorectal ring
- Columnar (1-2 cm)
- Between anorectal ring
and pectinate line
- Transitional zone (612 mm)

- Below pectinate line
- Nonkeratinizing
squamous cell (2 cm)
- Below anal verge
- Keratinizing
squamous cell
Abeloff, 2008
Anal Cancer
AJCC Staging
Anal Canal vs. Perianal Skin

Cancer
Tumors arising within the skin at or distal to the squamousmucocutaneous junction have been termed anal margin
cancers
The preferred term is perianal skin cancers, since they
behave biologically like skin cancers
These tumors are classified and treated as skin cancers
rather than anal canal cancers
In practice, if any portion of the tumor extends into the anal
canal, it is treated as anal cancer, otherwise it is treated as
skin cancer
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
PET is more sensitive than CT scan for identifying both the

primary tumor and lymph nodes, but it has a measurable
false positive rate compared to biopsy of inguinal nodes
FNA may be considered
As a negative FNA may be due to sampling error, excisional biopsy may
also be considered
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
Response assessed at 6 weeks

Good responders assigned to additional RT boost
Poor responders assigned to APR
Primary Endpoint: local failure at 6 weeks

Lancet 1996;348:10491054
UKCCCR ACT 1
Results
Lancet 1996;348:10491054
UKCCCR ACT I
Major Findings, 13-year Update
Compared to RT alone, the addition of

chemotherapy is associated with:
46% reduction in local failure (P < 0.0001)
No difference in OS (HR 0.86, P = 0.25)
29% reduction in deaths from anal cancer
(HR .71, P = 0.02)
Increased acute toxicity
No change in late toxicity
*British Journal of Cancer (2010) 102, 1123 1128
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)
*Due to risk of heme toxicity (thrombocytopenia)

Flam et al., J Clin Oncol 14:1527-39, 1996.
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
MMC (12 mg/m2 day 1) OR
CDDP (60 mg/m2 day 1 and 29)
80% power to detect 5% change in complete response
2nd randomization: Maintenance chemotherapy

consisting of two cycles of 5FU/CDDP after CMT vs.
none, with endpoint of improving recurrence-free
survival
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4009)
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
J Clin Oncol 30, 2012 (suppl; abstr 4004)
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
Long-term update of U.S. GI Intergroup RTOG

9811 Phase III trial for anal carcinoma:
Concurrent chemoradiation with 5FU/Mitomycin, yields better disease-free and
overall survival than 5-FU/Cisplatin
Leonard L. Gunderson MD, MS, FASTRO
Mayo Clinic Cancer Center-Arizona, Scottsdale, AZ
U.S. GI Intergroup RTOG 9811

Treatment Schema
5-FU/Mitomycin 2 cycles
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
Primary Endpoint: disease-free survival

Disease-Free Survival
Disease-Free Survival (%)
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
234
218
204
181
144
121
59
57

Overall Survival
100
Overall Survival (%)
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
283
271
235
213
168
151
68
76

Conclusions
RT + 5-FU/MMC remains the standard of care for patients with
anal canal carcinoma
MMC has borderline statistical significance for CFS and LRF
(p=0.05 and 0.087, respectively).
Possible reasons for superiority of RT + 5-FU/MMC:
Concurrent RT + 5-FU/MMC more effective than RT+5-FU/CDDP
Neoadjuvant 5FU/CDDP
Delay to concurrent chemoradiation
Platin-induced radioresistance
Anal Cancer:
Radiation
Technique
Anal Cancer
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
J Clin Oncol 14:2527-2539, 1996
Anal Cancer
Dose Recommendations for Chemoradiation:
Uninvolved areas
30-40 Gy
T1 (less than 2 cm)
40-45 Gy
T2 (2-5 cm)
50-59 Gy
T3/4 (>5 cm)
59-66 Gy.
Minimize treatment breaks

HIV pts should be managed as non-HIV pts
Keep CD4 counts >> 200 to minimize acute toxicity
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%
Ajani et al., JAMA 299, 1914-21, 2008
Evolution of Radiation Technique

IMRT
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
Kachnic et al, IJROBP 2012
Contouring and Constraints for

IMRT
Gross Disease
Nodal Areas at Risk:
Inguinal
Internal & external iliac
Mesorectal (peri-rectal and presacral)
Rectum and associated mesentary are target, not
avoidance structures
RTOG 0529
Disease Status
PTVA Dose
(LN) PTV42-45-50-54 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
Dose-painted IMRT with 5-FU/MMC

forLRF
N+andIf DFS
the right
groin LN
are N+for
and
> 3 cm,
the (MMC
left groin
LN are N+ but <
Example
Two-year
are similar
to values
RTOG
98-11
arm)
3 cm, and the pelvic LN are clinically negative, then the respective LN
Similar Gr 2 GI/GU
acute
toxicity
RTOG-9811,
less
PTV
doses
are 54to
Gy,
50.4 Gy, and
45Gr
Gy2 skin and Gr 3 GI/GU
toxicity
Three CTVs
CTVA: peri-rectal, pre-sacral, internal iliac
CTVB: external iliac
CTVC: inguinal
The Anorectal RTOG atlas should be used to contour elective volumes:

http://www.rtog.org/LinkClick.aspx?fileticket=DgflROvKQ6w%3d&tabid=231
Kachnic et al. 2013
3/10/2014
207
RTOG 0529 - Results

IMRT Duration/Interruptions
Median RT duration 43 days (range 32-59) vs. 49 days
(range 4-100) on the MMC arm of 9811 (P < 0.0001)
Treatment breaks due to toxicity needed in 49%, as

compared to 61% on the MMC arm of 9811 (P = 0.10)
Median duration of treatment break due to toxicity = 0 days

(range 0-12), as compared to 3 days (range 0-33) on the
MMC arm of 9811 (P = 0.0037)
Univariate Predictors of
Local-Regional Failure on 0529
Variable
Comparison
Gender
Female vs. Male
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
45-year-old female anal SCC, T3N0M0.

Karnofsky performance score (KPS) 80
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
3/10/2014
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
If > 1cm, and cirrhotic: 2 classic

enhancements on 3 phase CT or MRI
late arterial phase and portal venous
phase (arterial hyper-enhancement with
washout in venous phase)
Otherwise require FNA or core biopsy
MDC review, hepatitis panel, AFP,
PT/PTT/INR, Chest CT, bone scan
Bruix, Hepatology 2005
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
Dawson, SRO, 2011
HCC BCLC: Where RT Fits
Can Radiation Control HCC with

Portal Vein Thrombosis?
HCC portal vein thrombosis (PVT) invasion is a

strong prognostic factor
RT for HCC with PVT: High variability in series

Some studies combine RT with TACE
Prognostic factors: Child score, HCC burden, main
PVTT, complete occlusion, extrahepatic disease
Recanalization of portal vein thrombosis occurs

in ~ 50% of patients post RT
Median time to maximal response ~ 6 months

Median survival 4 13 months
Clinical Case: Resolution of

PVTT with RT
January 2009
AFP 10,000
Portal vein tumor thrombosis
September 2009
AFP 24
RT for HCC with Portal Vein Thrombus
Bullet One Here

Bullet Two Here
Bullet Three Here
Klein, Dawson, IJROBP, 2013
Toronto Phase I/II Study
102 HCC patients unsuitable for resection,

transplant, TACE or RFA
Hep B : Hep C: alcohol

Prior therapies
Portal vein thrombosis
Extrahepatic disease
Size: median
Median dose 36 Gy in 6 fractions (24 54 Gy, 6 #)
39% : 39% : 25%

50%
55%
12%
9.9 cm (2 43 cm)
Bujold, et al. Dawson, JCO April 2013
Toronto Phase I/II HCC Study

Overall Survival (n=102)
Median survival: 17 months
Survival by thrombosis
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
Hepatocellular Cancer: RTOG1112

Randomized phase III (n=368)
Primary endpoint: overall survival (median survival 10.5 to 14.5 mo)
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
Can Radiation Be Used Safely

in Child-Pugh B/C patients?
Toxicity lowest and survival best in Child

Pugh B7 versus > B7
Spare as much liver as possible
Mean liver (minus GTV)
Maximize the volume spared from RT
< 6 Gy in 5-10 fractions

>800 cc < 10 Gy (in 3-6 fractions)
Comparative trials needed
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
SBRT should be considered for T1/2 HCC

unsuitable for resection or RFA and as a bridge to
transplant
Best outcomes if < 6 cm and < 3 lesions
Randomized trials needed

RTOG1112 accruing please support
Opportunity for education, peer review and quality
improvement for RT centers
ASTRO Refresher 2014

THANK YOU!
Questions?
Gallbladder Cancer
3/10/2014
230
Gallbladder
Anatomy &
Histology
Lu, Decision Making in Radiation Oncology
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
Lymphatic invasion is seen in 45% at Dx

Spreads to hilar, and celiac LNs
At presentation, 40-50% have DM

Liver and peritoneum
Because seeding is common, FNA preferred over

incisional biopsy (avoid peritoneal drop mets)
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
T2, Stage IB: 30-40% (5-year OS)

May improve to 80% with radical surgery
Extended hepatectomy necessary if +HA or PV
T3, T4 or N1 Stage IIB and III: 0-15% (5-year OS)

Positive LN or liver or vascular invasion
Recommendation is for en bloc resection (difficult to
distinguish inflammation vs invasion)
Adjuvant therapy per SWOG S0809
Benefit adj Rx seen in LN+ or R1+ (Meta-analysis*)
3/10/2014
235
Gallbladder Cancer
Treatment of Locally Advanced Disease
Chemotherapy
Very little data
Phase III Mitomycin C/5-FU vs. observation
Included R0 and R1 patients

Mitomycin C and 5-FU improved survival from 14% to 26%
Subgroup analysis no OS benefit with R0 resection
Takada 2002 Cancer 95(8):1685
Concurrent 5-FU with XRT
Radiation
EBRT: Showed dose response (>54 Gy superior to
<54 Gy)
Kresl 2002 IJROBP 52(1): 167
IORT
Chao J Surg Onc 1991
Cholangiocarcinoma
3/10/2014
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
Pathology
Adenocarcinoma
No reliable markers to differentiate

ICC from a metastasis
Diagnosis of exclusion
Negative: lung (TTF1), colon
(CDX2),pancreas (DPC4)
Positive: biliary epithelium (AE1/
AE3; CK7+ and CK 20-)
Look for biliary dysplasia
Pre-operative Evaluation
CEA elevated in ~25% of cases

CA 19-9 elevated in ~50% of cases
AFP elevated in < 5% of cases
CEA or CA 19-9 are not sensitive enough
to diagnose cholangiocarcinoma (~50%)
Nehls, Sem Liv Dis, 2004
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
3/10/2014
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
Lu, Decision Making in Radiation Oncology
RT Dose Constraints (S0809)
ASTRO Refresher 2014

THANK YOU!
Questions?

Gastric Cancer11

Hochgeladen von

Dokumentinformationen

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Gastric Cancer11

Hochgeladen von

Copyright:

Verfügbare Formate

The Management of Gastrointestinal

ASTRO Spring Refresher Course

Thanks to the following contributors:

Review standard of care approaches for

T1b (invades submucosa)

45-50 Gy + 2 drug chemo

Patients: non-metastatic SCCa or ACa

Primary Endpoint: Survival

Herskovic, NEJM, 326: 1393-1393, 1992

Non-Operable Esophageal Cancer

Given the high rates of local failures,

Only SCCa of upper and

CRT (higher dose RT)

This study was designed to be a test of equivalence.

German Esophageal Trial

*In non-responders who attained a complete R0 resection, 3-yr OS increased to

CROSS Phase III Trial

Hagen, NEJM 366; 22, 2012

CROSS Phase III Trial

CROSS Phase III Trial

Pathologic complete response rate: 29%

Cross Phase III Trial

Stage IV Esophageal Cancer

RT/CRT is preferred over stent alone

Minsky, JCO 20:1167, 2002

Spinal cord max 45 Gy

Classic 3-D Technique

Long-term Outcomes Comparing 3-D to IMRT with

Lin et. al., IJROBP 2012

MD Anderson Experience: Acute Toxicity

Trimodality vs CRT alone pts evenly distributed [~50:50]

Years after diagnosis

Acute toxicities were nearly equivalent between

There were no differences in disease specific

IMRT was associated with longer overall survival

3D had increased cardiac and undocumented

Normal tissue sparing by IMRT may reduce late

Different treatment eras

A number of patients with unknown causes

University of Minnesota Reoperation Series: Patterns of Failure

*PS = Peritoneal spread

University of Minnesota Reoperation Series: Patterns of Failure

Median survival: 35 v 26 months

Macdonald et al., NEJM 2001

SWOG-Directed Intergroup Study

Smalley JCO 2012

Update: SWOG-Directed Intergroup Study 0116

(A) Overall survival (B) Relapse-free survival

Cunningham, NEJM 2006

Gastric Cancer Adjuvant Therapy

*24% of patients who died had LR prior to death

Gastric Adjuvant Therapy

XP: Capecitabine 1000 mg/m2 bid, CDDP 60 mg/m2

Lee et. al., JCO 2011

Lee, JCO 30:268-273, 2012

Lee, JCO 30:268-273, 2012

Gastric Adjuvant Therapy

ECC x 3 Gastrectomy ECC x 3

ECC: Epirubicin 50mg/m2, CDDP 60 mg/m2, capecitabine

S-1 Japanese trial

Spinal cord max 45 Gy

Mahmood et. al.;

Dose Volume Histogram

Compliments Bill Regine