radiotherapy-pancreatic cancer
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ΞΕΝΟΦΩΝ ΒΑΚΑΛΗΣ
ΑΚΤΙΝΟΘΕΡΑΠΕΥΤΗΣ – ΟΓΚΟΛΟΓΟΣ
ΙΑΤΡΙΚΟ ΚΕΝΤΡΟ ΑΘΗΝΩΝ
ΚΑΡΚΙΝΟΣ ΠΑΓΚΡΕΑΤΟΣΗ θέση του Ακτινοθεραπευτή Ογκολόγου
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
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 andPopulation 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
†
ΚΑΡΚΙΝΟΣ ΠΑΓΚΡΕΑΤΟΣ
• Έκταση της νόσου κατά τη διάγνωση:
– ΕΞΑΙΡΕΣΙΜΟΣ 20%
– ΤΟΠΙΚΑ ΠΡΟΧΩΡΗΜΕΝΟΣ ΑΝΕΓΧΕΙΡΗΤΟΣ 40%
– ΜΕΤΑΣΤΑΤΙΚΟΣ 40%
(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
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.
Patterns of Failure after Surgery
After surgery
• local relapse rate of 50 – 86%
and
•distant recurrence rate of 40 – 90%
Select between
Observation Chemotherapy
Chemoradiation Radiotherapy
Anything else to improve the patient’s
outcome?
15 $1 MILLION14 $500.00013 $250.00012 $100.00011 $50.00010 $25.0009 $16.0008 $8.0007 $4.0006 $2.0005 $1.0004 $5003 $3002 $2001 $100
Study(Year)
Number of
Patients
Enrolled Patients with R1
Resection (%)
Treatment Assignment
Median Survival Months
Treatment Assignment
Median SurvivalMonths
p value
GITSG(1985) 49 0
5-FU-based Chemoradiation
21.0
Observation
10.90.035
EORTC 40891 (1999) 114* 21
5-FU-based Chemoradiation
17.1
Observation
12.60.09
ESPAC-1(2004)
289 18
5-FU/Leucovorin Chemotherapy
20.1
No Chemotherapy
15.50.009
5-FU-based Chemoradiation
15.9
No Chemoradiation
17.90.05
RTOG 9704(2006)
388(Head
lesions)
34
Unknown in 25%
Gemcitabinethen
5-FU/EBRTthen
Gemcitabine20.5
5-FUthen
5-FU/EBRTthen5-FU16.9
0.09
CONKO 001(2007)
368 19Gemcitabine
22.8Observation
20.2 0.005
DFS = 13.4 DFS = 6.9 < 0.001
Randomized Trials of Adjuvant Therapy
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*First Phase III Adjuvant Pancreas Trial to Do So
trial RTOG 97-04 – RT QA
EORTC-40013-22012/FFCD-9203/GERCOR phase II study
Καλύτερη η ΧΗΜΕΙΟ ή ΧΗΜΕΙΟΑΚΤΙΝΟΘΕΡΑΠΕΙΑ;
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
Resected Pancreas CancerN= 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, +/- RTSecondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicityTissue acquistion/ correlative science
RANDOMIZE
2nd Randomization
+/-ChemoRT
RTOG contouring guidelines for adjuvant RT for pancreas
CTV must include:
Neoadjuvant Therapy
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
Accurate Pathology and Multimodality TherapyPancreaticoduodenectomy: 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 22Maj Comp
No 263 27 .01
Yes 93 22
R0 17 moR1 11 mo
ESPAC-1Ann Surg 2001
Raut, Ann Surg 2007;246:52-60 Local Failure (All pts): 8%
Preoperative Therapy
R1 Resection
YES 13%
NO 19%
The Importance of Neoadjuvant TherapyPancreaticoduodenectomy: Ductal Adenocarcinoma
M D Anderson (N = 360)
Raut, Ann Surg 2007;246:52-60 Local Failure (All pts): 8%
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
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
Treatment phase Break ~ 6 wks
CTXgem 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
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
Emerging Strategies for Locally advanced pancreatic cancer
Induction Chemotherapy Restage
Localized
ChemoXRT
Metastatic
2nd Line Rx or Best
Supportive Care
Maintenance
2 modern randomized trials
only 32 % received RT per protocolmore complete analysis
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
Modern Treatment Devices
CYBER-KNIFE
TR
ILO
GY
SY
NE
RG
Y
ELECTIVE NODAL IRRADIATION
the use of radiation therapy for elective treatment of regional lymph nodes is controversial for pancreatic cancer.
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
IMRT: Duodenal Sparing
SBRT: Duodenal Sparing
CYBERKNIFE
Locally Advanced PancreaticCancer(Gemcitabine, up to 1 Cycle allowed)* 2 week
break>2 week break
SBRT6.6 Gy x 5Mon-Fri
Gemcitabine Chemotherapy(3 wks on, 1 wk off)
Until toxicity or progression
Primary endpoint: Late GI Toxicity > 4 monthsSecondary: Tumor Progression Free SurvivalN=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
HDR-IORT: Pancreas
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