radiotherapy-pancreatic cancer

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