Transcript Radiation Therapy for Pancreatic Cancers

Radiation Therapy for
Pancreatic Cancers
Eyad Abu-Isa, M.D.
Assistant Professor, Radiation Oncology
University of Michigan/Providence Cancer Institute
February 28, 2015
Disclosures
• I have no actual or potential conflict
of interest in relation to this
presentation.
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Overview
• Radiation Basics
• Review of Literature
– Resected
– Unresectable
• Radiation Techniques
• Future Directions
• Questions
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Varian Truebeam
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How radiation therapy works
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Resected: Adjuvant Treatment
Study
Randomization
MS
(mo..)
3y OS
5y OS
GITSG 9173
ESPAC
CONKO-001
RTOG 97-04
RTOG 08-48
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GITSG 9173
Kalser and Ellenberg, Arch Surg 1985.
• Methods:
– Patients: 43 total patients enrolled
 22 patients randomized to no adjuvant treatment, and 21
to chemoradiation
 68% underwent Whipple, 32% had total
pancreatoduodenectomy. All but 2 patients had head
lesions.
– Tumors: All patients underwent resection of
localized pancreas cancer, and all had NEGATIVE
MARGINS.
 35% tumor confined to pancreas, 37% tumor extended
beyond the pancreas, 28% had nodal involvement
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GITSG 9173
• Methods:
– Treatment Arms:
 Arm 1) No adjuvant therapy
 Arm 2) Chemoradiotherapy arm:
 Chemotherapy: 5-FU (500mg/m2) given as bolus
infusion on day 1,2,3 of radiation courses one and two,
and once weekly for two years or until recurrence
documented.
 Radiation Therapy: Two 20 Gy courses, separated by
two weeks. Fraction dose not specified.
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GITSG 9173
Results:
– Adjuvant chemoRT significantly improves median
survival and DFS.
Adjuvant Tx
Median
Survival
(P=0.03)
2 yr
survival
Median DFS
(P=0.01)
None
11 months
15%
9 months
ChemoXRT
20 months
42%
11 months
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Resected: Adjuvant Treatment
Study
GITSG 9173
Randomization
Observation
ChemoRT
MS
(mo.)
3y OS
5y OS
11
20
15% (2y)
42% (2y)
5%
15%
ESPAC
CONKO-001
RTOG 97-04
RTOG 08-48
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ESPAC
Neoptolemos JP, Lancet 2001.
• Purpose: To clarify benefits of chemoRT and
maintenance chemo in adjuvant setting
• Methods: Prospective, multi-institutional, semirandomized, semi- controlled trial. Primary
endpoint: death.
– Patients: 541 patients were enrolled with histologically
proven ductal adenocarcinoma, with gross total resection
and no evidence of local spread or distant metastasis.
– Tumors: Allowed (+) margins
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ESPAC
• 2 x 2 factorial design (285 pt subset)
Treatment
# Patients
Median Survival
(mo.)
Chemoradiation
142
15.8
No chemoradiation
143
17.8 (NS)
Treatment
# Patients
Median Survival
Chemotherapy
146
20
No Chemotherapy
139
18 (SS)
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Resected: Adjuvant Treatment
Study
Randomization
MS
(mo.)
3y OS
5y OS
15% (2y)
42% (2y)
5%
15%
GITSG 9173
Observation
ChemoRT
11
20
ESPAC
ChemoRT
No ChemoRT
Chemo
No Chemo
16
18
22
20
10%
20%
21%
8%
CONKO-001
RTOG 97-04
RTOG 08-48
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CONKO-001
Oettle et al. JAMA 2007
• Phase III, multicenter, randomized, controlled trial
• Stratified for resection, tumor, and node status
• 368 pts with R0 (80%) or R1 pancreatic resection,
T1-4 (82% T3), N0-1 (70% N1)
• Observation vs Gemcitabine 1000 mg/m2 x 6
cycles (days 1, 8, 15 q4 weeks)
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CONKO-001
• Results: Gemcitabine
improved DFS
– Median f/u 53 months
– Median DFS: 13.4 vs 6.9
months (p<0.001)
– 1 year DFS: 58% vs. 31%
– Relapse: 74% vs 92%
– Median OS: 22.1 vs 20.2
months
– 5 year OS: 22% vs. 11%
(p=0.06)
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Resected: Adjuvant Treatment
Study
Randomization
MS
(mo.)
3y OS
5y OS
15% (2y)
42% (2y)
5%
15%
GITSG 9173
Observation
ChemoRT
11
20
ESPAC
ChemoRT
No ChemoRT
Chemo
No Chemo
16
18
22
20
CONKO-001
Observation vs
Gemcitabine
20
23
10%
20%
21%
8%
20%
37%
9%
21%
RTOG 97-04
RTOG 08-48
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RTOG 9704
• Conventional chemo-RT
• CI 5-FU (250 mg/m2 daily)x 3 wks
• chemo-RT (50.4 Gy with concurrent CI 5-FU)
• 3-5 weeks later: two-four week courses CI 5-FU (250 mg/m2 daily, with
a two week break b/w courses),
• Gemcitabine
• Three weekly doses of gemcitabine alone (1000 mg/m2 per week)
• Same chemoradiotherapy protocol as for the conventional
chemoradiotherapy arm
• 3 to 5 weeks later, three months of single agent gemcitabine (1000
mg/m2 weekly for three of every four weeks).
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RTOG 9704
Regine et al. JAMA 2008
• Results:
– Pancreatic head tumors(n=380) experienced significantly
improved survival with gemcitabine vs 5-FU:
• MS= 18.8 vs. 16.7 (p=0.09)
• 3YS= 31% vs. 21% (p=0.047)
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Resected: Adjuvant Treatment
Study
Randomization
MS
(mo.)
3y OS
5y OS
15% (2y)
42% (2y)
5%
15%
GITSG 9173
Observation
ChemoRT
11
20
ESPAC
ChemoRT
No ChemoRT
Chemo
No Chemo
16
18
22
20
CONKO-001
Observation vs
Gemcitabine
20
23
20%
37%
9%
21%
RTOG 97-04
Gem+5FU RT
5FU+5FU RT
17
20
31%
21%
22%
18%*
10%
20%
21%
8%
RTOG 08-48
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RTOG 08-48
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Resected: Adjuvant Treatment
Study
Randomization
MS
(mo.)
3y OS
5y OS
15% (2y)
42% (2y)
5%
15%
GITSG 9173
Observation
ChemoRT
11
20
ESPAC
ChemoRT
No ChemoRT
Chemo
No Chemo
16
18
22
20
CONKO-001
Observation vs
Gemcitabine
20
23
20% (3y)
37% (3y)
9%
21%
RTOG 97-04
Gem+5FU RT
5FU+5FU RT
17
20
31%
21%
22%
18%*
RTOG 08-48
Gem vs
Gem+chemoRT
??
??
??
??
??
??
10%
20%
21%
8%
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Unresectable Disease
•
Median survival for
untreated patients is ~4
months, and ~7 months
with palliative bypass
•
Modern chemotherapy
and radiation treatment
can prolong survival
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ECOG E4201
Loehrer PJ, J Clin Oncol 29:4105-4112, 2011
69 of planned 316 patients with unresectable
disease. Closed to slow accual.
– Arm 1) Gemcitabine alone 1000 mg/m2 x7 cycles
– Arm 2) RT 50.4/28 + gemcitabine 600 mg/m2, then
gemcitabine alone 1000 mg/m2 x5 cycles
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ECOG E4201 Results
Results:
– Median OS 9 months
vs. 11 months (SS)
– Toxicity: Grade 4 GEM
6% vs. GEM/RT 41%
(SS)
Conclusion: Gem+RT had
increased but generally
manageable toxicity, with
improved OS
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Neoadjuvant Therapy
•
No large, prospectively randomized studies for neoadjuvant
therapy.
•
Much of data from Phase I/II studies.
•
Potential benefits:
– Increase resectability rate
– Decrease local recurrence
– Decrease regional/metastatic spread through lymph nodes
– Better tolerated than adjuvant therapy with higher numbers of patients
completing intended treatment
– Select out patients with rapid disease progression/aggressive tumor
biology and spare them the morbidity of Whipple procedure
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MDA Experience
Breslin, Ann Surg Onc, 2001
•
Prospective study of 132 consecutive patients who received preop
chemoradiation followed by Whipple
•
RT:
– 45.0 or 50.4 Gy radiation at 1.8 Gy per fraction in 28 fractions or
– 30.0 Gy at 3.0 Gy per fraction in 10 fractions
•
Chemo: concomitant infusional chemotherapy (5-fluorouracil, paclitaxel,
or gemcitabine).
•
Then restaging studies--> if no evidence of disease progression, then
Whipple.
•
Results:
– 2YS 40% and MS was 21 months, despite 43% requiring vascular
resections
– Rate of clear resections: 88%
– Rate of local recurrence: 6%
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Radiation Planning
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Motion assessment/control
• Methods of diaphragmatic
motion control
– ABC breath hold (if
tolerated) – scan on
expiration
– Others use abdominal
compression
– If ABC not tolerated, 4D
CT to accurately account
for motion
• Treatment planning CT
scan is fused with
diagnostic study (PET/CT,
MRI, CT)
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Radiation Techniques
• Avoidance organs: duodenum/small bowel, liver, kidneys,
spinal cord
• Pancreatic head lesions: include pancreaticoduodenal,
suprapancreatic, celiac nodes, porta hepatis, duodenal loop
• Body/tail lesions: pancreaticoduodenal, lateral
suprapancreatic, splenic hilar nodes
• Boderline/Unresectable patients: small field radiation to
gross disease only.
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Radiation Targets
Target
Pancreatic head
Pancreatic tail
Unresectable/Bo
rderline
Primary tumor
x
x
x
Positive LNs
x
x
x
Parapanc LNs
x
x
Pancduo LNs
x
x
Celiac/SMA LNs
x
x
Portal LNs
x
Splenic LNs
x
Avoidance organs: duodenum/small bowel, liver, kidneys,
spinal cord
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2D Radiation Techniques
AP field with blocking
for pancreatic head
lesions
Lateral
field with
blocking
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Intensity Modulated RT (IMRT)
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High activity low-dose rate brachytherapy
• Single or multiple high activity radioactive I-125
seeds are placed into a tumor under radiographic
guidance.
• Advantages over external beam:
– Low energy radiation emitted from inside out, meaning
high dose to tumors, with quick dose fall-off
– Continuous low dose radiation delivered over months,
potential biologic advantage
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HALDR
• 66 yo male with pancreatic tail
adenocarcinoma.
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Figure 2
B
X
S
K
Pancreas tail mass (red) and intended seed position (X). No
direct access in the axial plane due to obstruction by
kidney(K), spleen(S), and bowel(B) .
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Needle access plane (green transparency) 2.4 cm below
axial target slice
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S
K
Needles advanced in a non-axial superior direction at the
junction of the kidney and spleen.
After passage beyond the critical organ it is again possible to
angle the needle in the intended direction. Once past the organ
the needle can safely displace the organ (spleen in the example)
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Coaxial needle in position (blue arrow). Marker seed
in place (red arrow)
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Marker seed (red arrow) and radioactive seed (gold arrow)
near intended position
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Response to HALDR
Before
After
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Conclusions
• Pancreatic survival rates are low, highlighting the
need for future research.
• Role for adjuvant radiation treatment is
controversial, but with careful radiation planning
proper patient selection, and better systemic
therapy, a benefit may exist
• Radiation improves local control in patients with
borderline resectable and unresectable disease and
may impact survival.
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Thank you!
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