pancreatic cancer - jtl 2012

8/3/2019 Pancreatic Cancer - JTL 2012

1/65


2/65


3/65

Epidemiology

Risk Factors

Anatomy

Staging, Prognosis

Lymphatics / Pattern ofSpread Pathogenesis/Genetics and Histology

Presentation

Workup

Labs, Imaging

Management Surgical, Peioperative Resectable

Unresectable

Metastatic Disease

Palliation

Outline


4/65

Epidemiology

4th leading cause of cancer death in M&F (43K in 2010 in US) 9th most common Ca Western>Eastern AA>Whites

OS Resection: 48% (1-yr)

Unresectable: 23% (1-yr)

Incidence peaks @70-80s

5-year O

Sis lowestof any cancer

Most diagnosed at unresectable stage


5/65

Age Gender: M>F Race: AA>W Smoking

Ionizing Radiation Chemotherapy Obesity and Diet: animal fats Possible link to EtOH, Coffee use, Diabetes Family History (BRCA2)

Chronic pancreatitis Exposure to pesticides, benzene, dyes (2-

Naphthylamine, petrochemicals (gasloine)

Risk Factors


6/65

Pathogenesis/Genetics

7590%FTIs

EGFRRTKi

mOS +1mo

SHHi

8590%

50%

85% Ductal Adeno

Subtypes


7/65

Anatomy

75%

15% 10%


8/65

Anatomy


9/65

Anatomy


10/65

Anatomy


11/65

Staging/AnatomyAJCC 7th Edition (2009)

Primary Tumor:T1 - confined to pancreas, 2 cm or lessT2 - confined to pancreas, > 2 cmT3 - extends beyond pancreas

T4 - invades SMA or celiac axis

Regional Lymph Nodes:N0 - noN1 - yes

Distant Metastases:M0 - noneM1 - yes

Stage Grouping:IA - T1 N0IB - T2 N0

IIA - T3 N0IIB - T1-3 N1III - T4Any NIV - M1


12/65

Pattern ofSpread: LymphaticDrainage


13/65

Pattern ofSpread: Distant Disease 30% Liver and Peritoneum

Lung most common extra-abdominal Major sites of recurrence:

50-86% operative bed (local) Liver 20-60%

Peritoneal 23-36%


14/65

Silent Disease

Most present as painless masses w/obstructive jaundice

Classic Triad- pain + jaundice + weight loss

Symptoms:

Jaundice

Pain in upper abdomen or back (dull or burning)

Floating stools w/especially abd odor

Weakness, Loss ofAppetite, N/V

Diabetes diagnosed 2 yrs prior to dx in >50%

PE findings (late): Palpable L SCV = Virchows node,

Periumbilical LN = Sister Mary Josephs node,

Palpable Gallbladder = Courvoisiers sign,

Migratory thrombophlebitis = Trousseaus sign

Presentation


15/65

Physical Exam Labs: CBC, CMP, LFTs w/GGT, Amylase, Lipase, Direct and

Indirect bilirubin, CA19-9, CEA

Biopsy: ERCP

EUS Sens 75%Spec 75% CT guided FNA

Laparoscopy

Imaging CT Triphasic thin slice

MRI w/w/o contrast

PET/CT 87%Sens for Mets Octereotide imaging if NE

MRCP

FDG-PET

Consider Angiogram

Workup


16/65

Workup Staging Studies


17/65

Preop Biliary drainage for obstructive lesions?

Presence of jaundice preop +s complications Does preop drainage reduce post op comp?

Randomized Multicenter Trial

1o Outcome: Complications w/in 120d

Results:

Complication Rate: Preop Decompression: 47%

Surgery Alone: 37% (SS)

No Difference in OS, hospital stay

Preop Jaundice Empiric antibiotics if concern forcholangitis

Management

Preoperative biliary drainage for cancer of the head of the pancreas. van der Gaag NA, Rauws EA, van Eijck CH, Bruno MJ, van der HarstE,Kubben FJ, Gerritsen JJ, Greve JW, Gerhards MF, de Hingh IH, Klinkenbijl JH, Nio CY, de Castro SM, Busch OR, van Gulik TM, Bossuyt PM,Gouma DJ. NEJM. 2010 Jan 14;362(2):129-37.


18/65

Chronic Pancreatitis Autoimmune Pancreatitis

Differentiate w/Ig levels

Islet cell/neuroendocrine cancer

Cystic adenomas, papillary cystic neoplasms (e.g.,intraductal papillary mucinous tumor)

Lymphoma

Acinar cell carcinoma

Metastatic cancer.

CA 19-9 may be elevated in bengin pancreatic pathology

Differential Diagnosis


19/65

NCCN criteria for resectability:

Resectable - no distant mets, clear fat plane around celiac/SMA,patentSMV

Borderline Resectable - severe unilateral SMV/portal impingement,abutSMA (


20/65

Imaging Resectability


21/65

Imaging Resectability


22/65

Surgical Evaluation: Head/Body

Head/Body lesions

Pancreaticoduodenectomy/Whipple Procedure:

Resected: Pylorus sparing antrectomy vs. classic antrectomy >40% removed

Cholecystectomy, Choledochectomy, Parrtial Pancreatectomy

Reconstructed:

Pancreaticojejunostomy, choledochojejunostopmy, gastrojejunostomy


23/65

Surgical Evaluation: Tail

Tail lesions:

Distal pancreatectomy and splenectomy

Cholecystectomy

Roux-en-Y hepaticojejunostomy

Vol (- )s

morbidity

R0: No evidence of microscopic or macroscopic tumor

R1: 1 cell w/in 1mm is considered + margin

R2: gross residual disease

Margins

Volume

Lieberman MD, Lilburn H, Lindsey M, Brennan MF. Relation of perioperative deaths to hospital volume among patients undergoing pancreaticresection for malignancy. Ann Surg 1995; 222:638-645.


24/65

Vein Reconstruction

- Results are varied

- Likely that small selected population of patients will benefit

- Japan improves OS, US/UKshows opposite

- Ongoing study @ Hopkins w/299 patients:

- no SS diff @ 1,3,5 yrs

- Should not be considered routine

Tseng,JF, Raut CP, Lee JE, et al. Pancreaticoduodenectomy w/vascular resection: margin status & OS . J GastrointestSurg 2004:8;935-949.

Extended Lymphadenectomy


25/65

Should only be carried out if possibility for R0 resection

No benefit to extended lymphadenectomy Definitive CRT is not equivalent

Resectable

Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part3: update on 5-year survival. Riall TS, Cameron JL, Lillemoe KD, Campbell KA, Sauter PK, Coleman J, Abrams RA, Laheru D, Hruban RH, Yeo CJ.J GastrointestSurg. 2005 Dec;9(9):1191-204; discussion 1204-6.

Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: final results of a randomized multi-institutional trial.Doi R, Imamura M, Hosotani R, Imaizumi T, Hatori T, Takasaki K, FunakoshiA, Wakasugi H, Asano T, Hishinuma S, Ogata Y, Sunamura M, Yamaguchi K,Tanaka M, Takao S, Aikou T, Hirata K, Maguchi H, Aiura K, Aoki T, Kakita A, Sasaki M, Ozaki M, Matsusue S, Higashide S, Noda H, Ikeda S, Maetani S, YoshidaS; Japan Pancreatic Cancer Study Group.

Surg Today. 2008;38(11):1021-8. Epub 2008 Oct 29.

Prognosis s/p Definitive Resection

1o predictor: Lymph Node Ration = # LN+ / Total # LN LNR = 0 25 mo

LNR < 0.2 22 mo

LNR 0.2-0. 4 15 mo

LNR > 0.4 12 mo

Margin status

Grade of lesion


26/65

Pattern of Failure s/p Definitive Resection Local failure: 50-80%, sole site of failure ~25% Regional Failure: para-aortic LN 21%

Distant Failure: Liver failure ~50%, commonly together with local failure, rarely as

sole site Peritoneal failure ~30% Nearly always concurrent w/local failure

US has been centered on management of local disease Cant see the forest for the trees

Europes care has been focused on management of distant disease

Cant see the trees for the forest

Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. (Pawlik TM, Surgery. 2007 May;141(5):610-8.

US & European Management


27/65

Treatment ParadigmResectable

Definitive Resection Obs vs. Adj CRT + Maint

Definitive Resection CRT+Maint (Gem vs. 5FU)

Defintive Resection Obs vs. Adj CRT (no Maint)

Definitive Resection Obs vs. Adj Chemo vs. Adj CRT+/-Maint

Definitive Resection Obs. Vs. Adj Gem

Borderline Resectable

Neoadjuvant CRT Reassessment for resection

UnresectableConsider prophylactic duodenal bypass, stenting

Locally Advanced: Definitive CRT

Metastatic


28/65

Treatment Paradigm: ResectableResectable

Definitive Resection Obs vs. Adjuvant CRT + Maint

1985 GITSG 9173

Definitive Resection CRT+Maint (Gem vs. 5FU)

RTOG 97-04

Definitive Resection Obs vs. Adj CRT (no Maint)

EORTC 40891

Definitive Resection Obs vs. Chemo vs. CRT+/-Maint

ESPAC-1Definitive Resection Obs. Vs. Adj Gem

CONKO-001

Definitive ResectionAdj 5FU vs. Gem

ESPAC-3


29/65

Resectable

GITSG- Kalser, Arch Surg 1985;120:899-903

Randomized No

Stratification

Early

Comparison: R

Concurrent Adj CRT

(5FU) + Maint vs. Obs

Patients

43

ECOG

0-3

T Stage

35%T2,

37%T3

Location

95% Head

5% Body

LN Status

28% LN+

Surgery

68% Whipple

R0v.R1 NR

RT

40Gy Split

Course

Chemo

5FU Bolus 500mg/m2

d1-3 qWkly x 2 yrs 2yr OS:43%/20 movs.

18%/11 mo

OS

43%/20mo

vs.

18%/11mo

DFS

11mo vs. 9mo

Recurrence

LR: 86% vs. 71%

Hepatic: 50% vs. 32%


30/65

Null: 1 doesn't equal 2

Null: 1 isnt less than 2


31/65

Meanwhile in Europe.


32/65

Resectable

EORTC 40891 - Klinkenbijl, Ann Surg 1999;230:776-84

2yr OS:

43%/20 movs.

18%/11 mo

Randomized Stratification

by Inst &

Location

Comparison: R

Concurrent Adj CRT

(5FU) vs. Observation

Patients

218

ECOG

0-2

T Stage

T1-T2

Location

55% Head

45% Periamp

LN Status

23% LN+

Surgery

25% R1

75% R0

RT

40Gy Split

Course

Chemo

5FU Bolus 500mg/m2

d1-3 qWkly

2yr OS (A v. O)

51%/24.5mo vs. 41%/19mo

Panc:34%/17 vs. 26%/13mo

PeriAmp:67%/39.5 vs. 63%/40.1mo

DFS

NR

Recurrence

NR


33/65

Resectable

EORTC 40891 - Klinkenbijl, Ann Surg 1999;230:776-84

PeriAmp- 2yr OS:

67%/39.5vs.

63%/40.1mo

Panc- 2 yr OS:

34%/17vs.

26%/13mo


34/65

Sample Size Calculation:

Type 1 Error: .025Power = .8Survival Rate Group 1: 43%Survival Rate Group 2: 18%

1:1 Randomization

= Sample Size Needed 119

If one-sided only need 98

https://biostatistics.mdanderson.org/SoftwareDownload/


35/65

Resectable

ESPAC1 Neoptolemos, Lancet 2001;358:1576

NEJM 2004;350:1200-1210

(+/-)

Randomized

2 x 2 factorial

Stratified by R,

T, N stage

Comparison: R

Chemo vs. CRT vs.

CRT+Maint vs. Obs

Patients

289

ECOG

NR

T Stage

NR

Location

NR

LN Status

78% LN+

Surgery28% R1

72% R0

RT40Gy Split

Course

Chemo5FU Bolus 500mg/m2

d1-3 qWkly x 2 yrs

OS

43%/20mo

vs.

18%/11mo

DFS

11mo vs. 9mo

Recurrence

LR: 86% vs. 71%

Hepatic: 50% vs. 32%

Chemo vs. No Chemo - 5yr OS21%/20.1mo vs. 8%/15.5mo

CRT vs. No CRT - 5yr OS10%/15.0mo vs. 20%/17.9mo)


36/65

ResectableESPAC1 Neoptolemos, Lancet 2001;358:1576 NEJM 2004;350:1200-1210


37/65

ResectableESPAC1 Neoptolemos, Lancet 2001;358:1576 NEJM 2004;350:1200-1210

72

CRT+Maint

103

CRT

166

Chemo

200

Obs

The Plan

How things shouldof been compared

How thingswere compared

>35% randomized toNo tx got tx that wasunspecified


38/65

Factorial Clinical Trial DesignIntention: + Efficiency of trials

Assumption: No interactions b/n arms (+ or -)Comparisons:1 vs. 2, 1 vs. 3, 1 vs. 42 vs. 3, 2 vs. 43 vs. 4

If 1 has any component of 2ness or visa versathen needs to be re-powered!

i.e. Chemo vs. ChemoRadiationAdj Chemo vs. Adj Chemo + MaintChemoRT vs. ChemoRT + Maint

Bayesian Design and Analysis of 2x2 Factorial Clinical Trials Biometrics Vol 53, No 2 1997 pp. 456-

464Factoriaol design for Randomized Clinical Trials. Bria. Ann Oncol (2006) 17 (10): 1607-1608.


39/65

Who knows what actually happened?


40/65

Resectable

CONKO-001 Oettle, JAMA. 2007;297(3):267

Randomized

Phase 3

Stratified by R,

T, N stage

Comparison:

R Adj Gem vs. Obs

Patients368

KPS>50%

T Stage86%

T3-4

LocationNR

LN Status72% LN+

Surgery

80% RO,

20% R1

RT

NA

Chemo x 6C (q4wkC)

- Gem 1gm/m2 qWkly x 3/4wks

3yrOS (Gem v Obs)34%/22.1mo vs.

22.5%/20.2mo

DFS+'d SS in all

subsets

RecurrenceLR: 34 v. 41%

DM: 56% v. 49%


41/65

Resectable

RTOG 9704 Regine JAMA. 2008;299(9):1019

Randomized

Phase 3

Stratified by R,

T, N stage

Comparison:

R CRT (5FU vs. Gem)

Patients451

KPS>60%

T StageT1-4

Location85% Head

15% Bod/Tail

LN Status65% LN+

Surgery

35% R1

65% R0

RT

45Gy/25fx

to tumor bed

& regional

LNs; 5.4Gy/3

boost to

tumor bed

Chemo

- 5-FU(250mg/m2/d) CI qd

concurrentw/RT

- 5FU 250mg/m2/d CI x 3wk

pre ChRT & x12wk post

- Gem 1gm/m2 wkly x 3wks

pre ChRT & post x12wk

3yr OS Head

Gem 31%/20.5mo

vs.

5FU 22%/16.9mo

DFS

11mo vs.

9mo

Recurrence

LR: 23-28%

RF: 8%

DM: 71-77%

3yr OSGem vs. 5FU31%/20.5mo

vs5FU 22%/16.9mo

15x more likely to have G4 Tox, 5x more Heme tox


42/65

Resectable


43/65

Resectable

ESPAC3 Neoptolemos , ASCO 09Abstr, Vol27, No18S

Randomized

Phase 3

Stratified by R

, Country

Comparison:

Chemo (5FU vs. Gem) vs.

Obs (closed)

Patients1088

KPSNR

T StageT1-4

LocationNR

LN Status72% LN+

Surgery

R0 65%

R1 35%

RT

NONE

Chemo X 6mo

- 5FU 425mg/m2/d bolus d1-

5 x 4wk

- Gem 1gm/m2 d1,8,15 x 4wks

mOS (5FU vs. Gem)23.0mo vs 23.6mo

NS

DFSNR

RecurrenceNR

More GI side effects w/5FU, More hematologic Tox w/Gem

Toxicity


44/65

Resectable

EORTC 40013 Van Laethem, JCO 2010 28(29):4450

Randomized

Phase 2

Stratified by

Inst, LN, PS

Comparison:

Adj Gem vs. Gem CRT

Patients90

KPS0-2

T StageT3>2>

1

LocationHead only

LN Status70% LN+

Surgery

R0 only

RT

50.4Gy

/ 28fx

Chemo

-Gem 1gm/m2 qWk 3/4wk q4wk x 4C

-Gem 1gm/m2x2C300mg/m2w/RT

mOS 2yr G v. GCRT

50.2%/23.4mo vs50.6%/24.3mo NS

DFS

10.9 v.12.4mo

Recurrence

Gem v. GemCRTLR: 24 v. 11%

L&DM: 13 v.20%

DM: 40 v. 42%

G4 tox4.7% in GemCRT arm v. 0% in Gem aloneToxicity


45/65

RTOG 0848/EORTC-40084-22804

1000mg/m2 qwk 3/4wkq4wk C x5C

1000mg/m2 qwk 3/4wkq4wk C x5C


46/65


47/65

Retrospective Analysis of GERCOR Phase 2/3

Huguet JCO 2007, 25:326-331


48/65

Treatment Paradigm: Borderline Resectable

Borderline ResectableSurgery

Neoadjuvant CRT

Reassess for RClinical Trial


49/65

BorderlineResectable

MD And Evans, JCO 08, Vol26, No21Single

Arm

Phase 2

Stratified

NA

Gem Concurrent w/30Gy/10fx

Restaging Whipple

Patients86 KPS>70% T StageT1-3 LocationHead LN Status*38% LN+

Surgery R0 or R1:(11%)

87% Rsctbl, 13% UnR

75% R, 4% off protocol

20% Progressed

RT

30Gy

/ 10fx

Chemo

- Gem 400mg/m2

qwk x 7 wks

5 yr mOS27%/22.7mo ALL,36%/34mo Rsctd,

0%/7.1moUnRsctd

DFS15.4mo

RecurrenceLR: 11%

DM: 60% (41% liver)

No CRT deaths, 9% Periop Death

Toxicity


50/65


MD And Evans, JCO 08, Vol26, No21


51/65


MD And Evans, JCO 08, Vol26, No21

71% 74%


52/65

Treatment Paradigm: Unresectable

UnresectableConsider prophylactic duodenal bypass, stenting

Locally Advanced: Consider Definitive CRT vs. Chemo


53/65

Treatment Paradigm: Metastatic

Metastatic:Management based on KPS/ECOG

Best supportive care

Palliative stenting/surgery Chemo:

Gem

GemOx

FOLFIRINOX


54/65

Metastatic

ECOG 6201 Poplin JCO 2009;27(23):3778

Randomized

Phase 3

Stratified by

PS, R, T, N stage

Comparison:

Chemo

(Gem, Gem FDR, GemOx)

Patients832

KPS0-2

T StageAll

Location>90%

Metastatic

LN StatusNR

Surgery

NA

RT

NA

Chemo

- GEM 1gm/m2 wkly for 7/8wks x 1C

wkly x 3-4C

- GEM FDR 1.5gm/m2 d1,8,15 q4wks

-GEM1gm/m2 + Ox 100mg/m2 d2 q2wks

mOS & 1 yr OS%

GEM vs. GEMFDR vs. GEMOX

16%/4.9mo vs. 21%/6.2mo vs.

21%/5.7mo (SS)

DFS Recurrence

Toxicity


55/65

Metastatic

ACCORD4 Conroy NEJM 2011;364(19):1817

Randomized

Phase 2/3

Stratified by

Center, PS, T

location

Comparison:

Chemo

(Gem v. FOLFIRINOX)

Patients342

KPS0-1

T StageAll

LocationMetastatic

60% body/tail

LN StatusNR

Surgery

NA

RT

NA

Chemo

- GEM 1gm/m2 wkly for 7/8wks wkly -

FOLFIRINOX q2wks x 6mo

FOL vs. Gem

mOS 11.1mo v. 6.8mo

DFS

mPFS 6.4 v.3.3mo

Recurrence

ORR 31.6% v.9.4%

Toxicity


56/65

Treatment RadiationGTV define by Preop imaging

CTV -1-1.5cm extension of : Celiac axis, SMA and PV ROIs should be expanded by 1.0-1.5 cm in all directions.

Aortic ROI should be expanded asymmetrically to include the prevertebral nodal regions from the top of the PJ, PV, or CA (whichever ismost superior) to the bottom of L2 (or L3 if GTV location low, see above section). 2.5 to 3.0 cm to the R, 1.0 cm to the L, 2.0 to 2.5 cmanteriorly, 0.2 cm posteriorly.

Delineated clips may be expanded by 0.5 1.0 cm in all directions or used without expansion.

Merge the above ROI/ROI expansions (CA, SMA, PV, GTV, Aortic, PJ, , clips) with the following constraints and notes:

The post margin should follow the contour of the ant aspect of the vertebral body w/o actually including more than 0.10 cm of the anteriorvertebral body ant edge.

If the PJ cannot be identified, the CTV should be generated without it.

If the surgeon has created a pancreaticogastrostomy, do not include it into the CTV.

If the CTV with the noted expansions protrudes into a dose limited normal organ such as the liver or stomach, the CTV should be edited tobe adjacent (may touch the edge of) the relevant structure.

di i


57/65

Treatment RadiationTolerances

Kidney L&R D50%


58/65

Post Tx Management

Consider pancreatic enzyme replacementPalliative care consult

LMWH for concern for thromboembolic disease

E d


59/65

End

ESPAC3 t i it


60/65

ESPAC3 toxicity

ECOG 6201 T


61/65

ECOG 6201 Tox

L h ti D i


62/65

Lymphatic Drainage

2/24

24/1

11/16

19/10

22/10

7/10

53/3

36/3

8/8

1/42/36

4/10

10/15

23/1

13/10

A

B/CA : JPS LN Station #B: Head Ca % LN Met

C: Body/Tail Ca % LN Met


63/65


64/65

Hunter, Ben Josef IJROBP- Dec 2011


65/65

pancreatic cancer - jtl 2012

Documents