This document discusses pancreatic cancer and its treatment. It begins by stating that pancreatic cancer is most commonly diagnosed as locally advanced or metastatic. It then discusses the role of surgery, chemotherapy, and radiation therapy in the treatment of pancreatic cancer. It notes that the majority of surgically treated patients will have a recurrence, with a median survival of 15-20 months. The value of adjuvant and neoadjuvant therapy is debated. The document summarizes several clinical trials investigating chemotherapy and chemoradiation as adjuvant treatment after surgery. It also discusses neoadjuvant therapy and its potential advantages over adjuvant therapy. Emerging strategies discussed include induction chemotherapy followed by localized chemoradiation or second line therapy. The document concludes by describing modern radiation

1. ΞΕΝΟΦΩΝ ΒΑΚΑΛΗΣ
ΑΚΤΙΝΟΘΕΡΑΠΕΥΤΗΣ – ΟΓΚΟΛΟΓΟΣ
ΙΑΤΡΙΚΟ ΚΕΝΤΡΟ ΑΘΗΝΩΝ
ΚΑΡΚΙΝΟΣ ΠΑΓΚΡΕΑΤΟΣ
Η θέση του Ακτινοθεραπευτή Ογκολόγου

2. Δηλώνω ότι δεν έχω
(προσωπικά ή ως μέλος εργασιακής/ερευνητικής ομάδας) ή μέλος της
οικογένειάς μου οποιοδήποτε οικονομικό ή άλλου είδους όφελος από
τις εταιρείες/επιχειρήσεις που διοργανώνουν /χρηματοδοτούν την άνω
εκδήλωση

3. 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
†

7. ΚΑΡΚΙΝΟΣ ΠΑΓΚΡΕΑΤΟΣ
• Έκταση της νόσου κατά τη διάγνωση:
– ΕΞΑΙΡΕΣΙΜΟΣ 20%
– ΤΟΠΙΚΑ ΠΡΟΧΩΡΗΜΕΝΟΣ
ΑΝΕΓΧΕΙΡΗΤΟΣ 40%
– ΜΕΤΑΣΤΑΤΙΚΟΣ 40%

8. (Staley’s Ταξινόμηση, 1996) [1]
Εντοπισμένος/Εξαιρέσιμος 15--20 μήνες 5-20%
Τοπικά Προχωρημένος 6-10 μήνες 0%
Μεταστατικός 3-6 μήνες 0%
] Staley CA, et al. Pancreas 1996; 12:373-80.
5-ετης (%)Μέση Επιβίωση

10. ΚΑΡΚΙΝΟΣ ΠΑΓΚΡΕΑΤΟΣ
ΘΕΡΑΠΕΙΑ
• η πλειοψηφία αυτών που υποβάλλονται σε
χειρουργική εξαίρεση υποτροπιάζουν, μέση
επιβίωση : 15-20 μήνες)
- 2% ιώνται με την εγχείρηση
• η αξία της μετεγχειρητικής (“adjuvant”) ή
προεγχειρητικής (“neoadjuvant”) θεραπείας
αποτελεί θέμα αμφισβήτησης.

11. Patterns of Failure after Surgery
After surgery
• local relapse rate of 50 – 86%
and
•distant recurrence rate of 40 – 90%

12. Select between
Observation Chemotherapy
Chemoradiation Radiotherapy
Anything else to improve
the patient’s outcome?
15 $1 MILLION
14 $500.000
13 $250.000
12 $100.000
11 $50.000
10 $25.000
9 $16.000
8 $8.000
7 $4.000
6 $2.000
5 $1.000
4 $500
3 $300
2 $200
1 $100

13. Study
(Year)
Number
of
Patients
Enrolled
Patients
with R1
Resection
(%)
Treatment
Assignment
Median Survival
Months
Treatment
Assignment
Median Survival
Months
p value
GITSG
(1985) 49 0
5-FU-based
Chemoradiation
21.0
Observation
10.9
0.035
EORTC 40891
(1999) 114* 21
5-FU-based
Chemoradiation
17.1
Observation
12.6
0.09
ESPAC-1
(2004)
289 18
5-FU/Leucovorin
Chemotherapy
20.1
No
Chemotherapy
15.5
0.009
5-FU-based
Chemoradiation
15.9
No
Chemoradiation
17.9
0.05
RTOG 9704
(2006)
388
(Head
lesions)
34
Unknown
in 25%
Gemcitabine
then
5-FU/EBRT
then
Gemcitabine
20.5
5-FU
then
5-FU/EBRT
then
5-FU
16.9
0.09
CONKO 001
(2007)
368 19
Gemcitabine
22.8
Observation
20.2 0.005
DFS = 13.4 DFS = 6.9 < 0.001
Randomized Trials of Adjuvant Therapy

14. Entry Criteria
Quality Assurance of Radiation Therapy
Performed
RTOG 9704 / US Intergroup Phase III Postop Adjuvant Study
*First Phase III Adjuvant Pancreas Trial to Do So

15. trial RTOG 97-04 – RT QA

16. EORTC-40013-22012/FFCD-9203/GERCOR phase II study
Καλύτερη η ΧΗΜΕΙΟ ή ΧΗΜΕΙΟΑΚΤΙΝΟΘΕΡΑΠΕΙΑ;

18. Post-operative 5-FU-based Chemoradiation
(CXRT) for resected pancreatic cancer
non-randomized trials
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

20. Resected
Pancreas
Cancer
N= 952 Gemcitabine
+ Erlotinib x 4
Ongoing trial phase III - Adjuvant therapy
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

22. RTOG contouring guidelines for
adjuvant RT for pancreas
CTV must include:

23. Neoadjuvant Therapy

24. 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

25. 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%

26. 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%

27. ΠΛΕΟΝΕΚΤΗΜΑΤΑ NEOADJUVANT
• Μικρότερος χρόνος θεραπείας (62 vs. 99 ημ)-υπερκλ
• Αυξημένη ακτινοευαισθησία-καλύτερη οξυγόνωση
• Δεν αναβάλλεται ή δεν καθυστερεί η προγρ. Θεραπεία
• Χαμηλότερο ποσοστό + ορίων εκτομής – υποσταδιοπ.
• Αποφυγή εγχείρησης σε ασθ. με επιθετική νόσο (26%)
• Μείωση περιτοναϊκών εμφυτεύσεων
• Λιγότερες παρενέργειες V adjuvant
Spitz et al, 1977
Hoffman et al, ECOG study, 1988
Pisters et al, 1998

28. Neoadjuvant therapy
• No randomized studies comparing to
adjuvant
• Small, Phase II, mostly single instituiton
• 5-fu and Gemcitabine chemoradiation have
been studied
• Neoadjuvant chemoradiation can be given
safely without excess surgical morbidity

30. 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

31. The first United States national trial of neoadjuvant therapy for
potentially resectable pancreatic cancer (ACOSOG Z5041) is open, and
eligible patients should be encouraged to enroll.
Gemcitabine-Erlotinib
Surgery
Gemcitabine-Erlotinib
No Radiotherapy

34. Emerging Strategies for
Locally advanced pancreatic cancer
Induction
Chemotherapy
Restage
Localized
ChemoXRT
Metastatic
2nd Line Rx or
Best
Supportive
Care
Maintenance

35. 2 modern randomized trials

42. only 32 % received RT per protocol
more complete analysis

44. Radiation Therapy
External Beam Radiation Therapy (EBRT) is currently used.
3D Conformal Radiation (3-4 Fields)
Intensity Modulated Radiation Therapy (IMRT) (3-10 fields)
Volumetric modulated arc therapy (VMAT)
Tomotherapy
Stereotactic Body Radiation Therapy (SBRT) (multiple fields)
Intraoperative radiation therapy (IORT)
brachy or electrons

45. Modern Treatment Devices
CYBER-KNIFE
TRILOGYSYNERGY

46. ELECTIVE NODAL
IRRADIATION
the use of radiation therapy
for elective treatment of
regional lymph nodes is
controversial for pancreatic
cancer.

47. 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 & RTOG 1201 for LAPC

49. IMRT: Duodenal Sparing
SBRT: Duodenal Sparing

51. CYBERKNIFE

55. 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

56. HDR-IORT: Pancreas