4. Five-year Relative Survival (%)* during Three Time Periods By Cancer Site
*5-year relative survival rates based on follow up of patients through 2003.
†Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.
Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2006.
Site 1975-1977 1984-1986 1996-2002
•All sites 50 53 66
•Breast (female) 75 79 89
•Colon 51 59 65
•Leukemia 35 42 49
•Lung and bronchus 13 13 16
•Melanoma 82 86 92
•Non-Hodgkin lymphoma 48 53 63
•Ovary 37 40 45
•Pancreas 2 3 5
•Prostate 69 76 100
•Rectum 49 57 66
•Urinary bladder 73 78 82
†
25. Gutt R et al. (2008) Adjuvant radiotherapy for resected pancreatic cancer: a lack of benefit or a
lack of adequate trials?
Nat Clin Pract Gastroenterol Hepatol doi:10.1038/ncpgasthep1301
Patterns of failure after resection of pancreatic cancer without adjuvant radiation
therapy or chemotherapy
31. Post-operative 5-FU-based
Chemoradiation (CXRT) for resected
pancreatic cancer
Institution Time
Period
#
Patients
Median
survival
CXRT
Median
survival
No CXRT
P-
value
Mayo
Clinic
1975-
2005
466
(R0)
25.2 Mo 19.2 Mo 0.001
Johns
Hopkins
Hospital
1993-
2005
616
(R0 + R1)
21.4 Mo 14.4 Mo <0.001
Herman JM et al. JCO, 2008 Corsini MM et al. JCO, 2008
33. Meta-Analysis of Adjuvant Trials
Butturini G, et al. Arch Surg, 2008
R1
No chemoXRT
R1
With chemoXRT
HR 0.72
95% CI 0.47-1.10
34. Resected
Pancreas
Cancer
N= 952 Gemcitabine
+ Erlotinib x 4
US Intergroup/RTOG 0848
Gemcitabine
x 4 cycles
Stratification
₋ R0 vs R1 resection; T stage; N(+) vs N(-)
Primary Endpoint: Overall Survival +/- Erlotinib, +/- RT
Secondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicity
Tissue acquistion/ correlative science
R
A
N
D
O
M
I
Z
E
2nd
Randomization
+/-
ChemoRT
35. Standard adjuvant therapies
• USA – adjuvant chemotherapy + chemoradiotherapy
• Europe – adjuvant chemotherapy
Debate continues
38. resectable disease
Use high-quality dual phase helical CT imaging to
identify patients with truly resectable disease.
Restage patient prior to initiating adjuvant therapy with
CT imaging +/- CA19-9 level.
Deliver systemic therapy (gemcitabine-based) for a few
months, restage, and if R1 resection, consider
chemoXRT.
39. Author - Country Number
of
Patients
Margin +
Resection
Rate
Median
Survival
Independent
Prognostic
Factor
Winter-U.S. 1175 42% 14 m Yes
Richter-Germany 194 37% 12 m Yes
Kuhlmann-
Netherlands
160 50% NS Yes
Takai-Japan 89 47% 8 m Yes
Margin + Resections are Frequent and
Associated with Poor Prognosis
40. Accurate Pathology and Multimodality Therapy
Pancreaticoduodenectomy: Ductal Adenocarcinoma
M D Anderson (N = 360)
Variable No. Pts Med Sur p value
Overall 360 25
N0 174 32 .002
N1 186 22
R0 300 28 .03
R1 60 22
Maj Comp
No 263 27 .01
Yes 93 22
R0 17 mo
R1 11 mo
ESPAC-1
Ann Surg 2001
Raut, Ann Surg 2007;246:52-60
Local Failure (All pts): 8%
41. Preoperative
Therapy
R1 Resection
YES 13%
NO 19%
The Importance of Neoadjuvant Therapy
Pancreaticoduodenectomy: Ductal Adenocarcinoma
M D Anderson (N = 360)
Raut, Ann Surg 2007;246:52-60
Local Failure (All pts): 8%
42. ΠΛΕΟΝΕΚΣΗΜΑΣΑ NEOADJUVANT
• Μικπόηεπορ σπόνορ θεπαπείαρ (62 vs. 99 ημ)-ςπεπκλ
• Αςξημένη ακηινοεςαιζθηζία-καλύηεπη οξςγόνωζη
• Δεν αναβάλλεηαι ή δεν καθςζηεπεί η ππογπ. Θεπαπεία
• Χαμηλόηεπο ποζοζηό + οπίων εκηομήρ – ςποζηαδιοπ.
• Αποθςγή εγσείπηζηρ ζε αζθ. με επιθεηική νόζο (26%)
• Μείωζη πεπιηοναϊκών εμθςηεύζεων
• Λιγόηεπερ παπενέπγειερ V adjuvant
Spitz et al, 1977
Hoffman et al, ECOG study, 1988
Pisters et al, 1998
43. Recent Trials of Pre-Op Chemoradiation for
Resectable Pancreatic Cancer
44. Treatment phase Break
~ 6 wks
CTX
gem combo
Staging CT
Restaging
Dropout
Borderline Resectable PC
MDACC Treatment Approach
Restaging
Dropout
Chemo-XRT
OR
Classification
as Borderline
Katz MHG, et al. J Am Coll Surg. 2008;206(5):833-46
45. A multi-centre prospectively randomised phase II-
study of the Interdisciplinary Working Group
Gastrointestinal Tumours (AIO, ARO, and CAO).
Primary resection versus neoadjuvant
chemoradiation followed by resection for locally
resectable or potentially resectable pancreatic
carcinoma without distant metastasis. The
resection is followed by adjuvant chemotherapy in
both arms
46. Pre-Operative Therapy Selects Patients
Better than Upfront Surgery
● Avoids surgery in patients with rapidly progressive
disease (unfavorable tumor biology).
Avoids surgery in patients unable to tolerate the stress
of pre-operative therapy (those revealed to be unfit).
*Evans DB, et al. JCO, 2008
Protocol Regimen Number
of pts
Resection
Rate
Overall
Survival
MDA
98-020*
Gem/XRT 86 74% 34 mo
MDA
01-341^
Gem/Cis
Gem/XRT
90 66% 31 mo
^Varadhachary GR, et al. JCO, 2008
●Surgery was avoided in 25-35% of the
patients; their median survival was 7-10 mo.
●Local failure occurred in 10-25% of patients
undergoing resection; suggesting radiation
may have a role in preoperative setting.
48. CT-RT vs RT for
advanced pancreatic cancer: 2 RCTs
Mayo Clinic:
• N=64
• FU-RT vs placebo-RT
• Median survival
significantly better in CT-
RT arm (10.4 vs 6.3
months)
GITSG:
• N=194
• 3 arms: RT alone (60Gy)
vs CT-RT (40Gy) vs CT-
RT (60 Gy)
• Significantly improved
TTP & OS with CT-RT
• No significant difference
between high- & low-dose
CT-RT arms
Lancet 1969;2(7626):865-867.
Cancer 1981;48(8):1705-1710.
50. Chemoradiation > RT alone
• Medicare/SEER (Krzyzanowska, JCO 2003)
• Large, retrospective cohort
• 1696 patients treated between 1991-96
• Adjusted mean survival duration (weeks):
Chemoradiation 47
RT alone 29
Chemo alone 27
No therapy 15
• Supports the use of chemoradiation over either
modality alone
51. CT-RT vs CT for advanced
pancreatic cancer: 4 RCTs
ECOG:
• FU vs FU-RT (40Gy)
• No median survival
difference between the
2 arms
GITSG:
• SMF vs SMF-RT (54Gy)
• Significant improvement in
median survival for CT-RT
arm (9.4 vs 7.4 months)
J Natl Cancer Inst 1988;80(10):751-755.
J Clin Oncol 1985;3(3):373-78.
52.
53. Overall Survival
*stratified 2-sided log rank
ECOG 4201: Radiation plus gemcitabine versus
gemcitabine alone for patients with locally
advanced pancreatic cancer.
No benefit to XRT
here!
Benefit to XRT
GEM: Median Survival 9.2 Months (95% CI [7.8, 11.4]) -----------------------
GEM + Radiation: Median Survival 11.0 Months (95% CI [8.4, 15.5]) -----------------------
54. Selection Mechanism
Tumor behavior (Favorable vs Poor)
●ECOG 4201 demonstrates local control is only
relevant in patients with favorable biology.
●In locally advanced disease, chemotherapy can
identify patients with poor tumor biology and spare
them radiation (unlikely to be effective).
55.
56. 3Huguet F et al. JCO, 2007
MD Anderson1
318 Pts ChemoXRT 8 mo
Chemo ChemoXRT 12 mo
UCSF2
25 Pts
Induction Gem/Cis
28%Progressed
Cape/XRT 17 mo
10 mo
GERCOR3
181 Pts
Induction Chemo
29% Progressed
ChemoXRT 15 mo
Continued Chemo 12 mo
2Ko A et al. Int J Rad Oncol Biol Phys, 2007
1Krishnan S et al. Cancer, 2007
57. Emerging Strategies for
Locally advanced pancreatic cancer
Induction
Chemotherapy
Restage
Localized
ChemoXRT
Metastatic
2nd Line Rx or
Best
Supportive
Care
Maintenance
58. • Arm A: GEMCAP chemotherapy alone,
• Arm B: induction GEMCAP chemotherapy followed by GEM plus 50.4Gy
in 28 fractions,
• Arm C: induction GEMCAP chemotherapy followed by GEM plus 50.4Gy
in 28 fractions plus nelfinavir,
• Arm D: induction GEMCAP chemotherapy followed by GEM plus
59.4Gy in 33 fractions,
• Arm E: induction GEMCAP chemotherapy followed by GEM plus 59.4Gy
in 33 fractions plus nelfinavir.
SCALOP II
69. IMRT vs 3-D
Yovino et al. (2011)
IMRT significantly reduced the incidence of Grade
3-4 nausea and vomiting (0% vs. 11%) and
diarrhea (3% vs. 18%).
IMRT in the recently activated EORTC/US Intergroup/RTOG 0848
adjuvant pancreas trial
79. Locally
Advanced
Pancreatic
Cancer
(Gemcitabine,
up to 1 Cycle
allowed)*
2 week
break
>2 week
break
SBRT
6.6 Gy x 5
Mon-Fri
Gemcitabine Chemotherapy
(3 wks on, 1 wk off)
Until toxicity or progression
Primary endpoint: Late GI Toxicity > 4 months
Secondary: Tumor Progression Free Survival
N=60
Trial open at Stanford and Johns Hopkins. Memorial Sloan Kettering Pending.
Phase II Multi-Institutional Study of Stereotactic
Body Radiation Therapy for Unresectable Panceatic Cancer