upper gastrointestinal tract malignancies · 2012-04-30 · learning objectiveslearning objectives...

UPPERUPPERUPPER UPPER GASTROINTESTINAL GASTROINTESTINAL

TRACT MALIGNANCIESTRACT MALIGNANCIES

Michael G. Haddock M.D.Michael G. Haddock M.D.M Cli iM Cli iMayo ClinicMayo Clinic

ASTRO Spring RefresherASTRO Spring RefresherA il 13 2012A il 13 2012April 13, 2012April 13, 2012

DisclosureDisclosureDisclosureDisclosure•• Speaker at Imedex CME eventSpeaker at Imedex CME event•• Speaker at Imedex CME eventSpeaker at Imedex CME event

Learning ObjectivesLearning ObjectivesLearning ObjectivesLearning Objectives

•• Describe the indications for the use ofDescribe the indications for the use of•• Describe the indications for the use of Describe the indications for the use of radiotherapy and the appropriate radiotherapy and the appropriate radiotherapy regimens for treatment ofradiotherapy regimens for treatment ofradiotherapy regimens for treatment of radiotherapy regimens for treatment of upper gastrointestinal tract malignanciesupper gastrointestinal tract malignanciesD ib d di ti t h iD ib d di ti t h i•• Describe modern radiation techniques Describe modern radiation techniques and expected outcomes for patients with and expected outcomes for patients with upper gastrointestinal tract malignanciesupper gastrointestinal tract malignanciesupper gastrointestinal tract malignanciesupper gastrointestinal tract malignancies

PrePre--test Questiontest QuestionPrePre test Questiontest Question

•• When treating liver metastases with 60When treating liver metastases with 60•• When treating liver metastases with 60 When treating liver metastases with 60 Gy in 3 fraction SBRT, what is the best Gy in 3 fraction SBRT, what is the best dose limit parameter for the liver?dose limit parameter for the liver?dose limit parameter for the liver?dose limit parameter for the liver?a. V30Gy < 50%a. V30Gy < 50%b V15G < 50%b V15G < 50%b. V15Gy < 50%b. V15Gy < 50%c. 700 cc nml liver < 15 Gyc. 700 cc nml liver < 15 Gyd. 700 cc nml liver < 30 Gyd. 700 cc nml liver < 30 Gye. Mean liver dose < 25 Gye. Mean liver dose < 25 Gy

Upper GI MalignanciesUpper GI Malignanciespp gpp gOutlineOutline

•• Esophageal Cancer Primary TherapyEsophageal Cancer Primary TherapyEsophageal Cancer Primary TherapyEsophageal Cancer Primary Therapy•• Gastric Cancer AdjuvantGastric Cancer Adjuvant•• Pancreatic CancerPancreatic Cancer

•• Locally AdvancedLocally AdvancedLocally AdvancedLocally Advanced•• Surgical AdjuvantSurgical Adjuvant

•• Hepatobiliary MalignanciesHepatobiliary Malignancies•• CholangiocaCholangioca•• Liver metsLiver mets

EpidemiologyEpidemiologyp gyp gy2008 Worldwide Statistics2008 Worldwide Statistics

•• Eighth most common cancer worldwide Eighth most common cancer worldwide •• 482 300 new cases482 300 new cases•• 482,300 new cases482,300 new cases•• 406,800 deaths406,800 deaths

•• Squamous cell carcinoma in Asia and Squamous cell carcinoma in Asia and East AfricaEast Africa

•• Adenocarcinoma in the westAdenocarcinoma in the west

Jemal, Ca Cancer J Clin 61:69-90,2011

Estimated DeathsEstimated Deaths--WorldwideWorldwide

BreastLung & bronchus

458,400

427 400

Lung & bronchusLiver

951,000

478 300

MaleMale FemaleFemale

Lung & bronchus

Cervix uteri

Colon & rectum

427,400

275,100

288,100

Liver

Colon & rectum

Stomach

478,300

320,600

464,400

Stomach

Liver

273,600

217,600

EsophagusProstate

276,100

258,400

OvaryEsophagus

Pancreas

140,200

130,700

127,900

LeukemiaPancreas

Urinary bladder

143,700

138,100

112,300 a c eas

Leukemia

All sites but skin

,

113,800

3,345,800

y

Non-Hodgkinlymphoma

All sites but skin

,

109,500

4,225,700

Jemal: Ca Cancer J Clin 61:69-90, 2011

All sites but skin3,345,800All sites but skin 4,225,700

EpidemiologyEpidemiologyEsophageal Carcinoma U.S IncidenceEsophageal Carcinoma U.S Incidence

•• 16 980 new cases in U S in 201116 980 new cases in U S in 201116,980 new cases in U.S in 201116,980 new cases in U.S in 2011•• 14,710 deaths in U.S. in 201114,710 deaths in U.S. in 2011•• Incidence of ACA increased > 350%Incidence of ACA increased > 350%

•• 17% of esophageal cancers in 1970s17% of esophageal cancers in 1970s17% of esophageal cancers in 1970s17% of esophageal cancers in 1970s•• 60% of esophageal cancers in 199560% of esophageal cancers in 1995

↑↑•• Death rate in males Death rate in males ↑↑ 7% 1990 to 20077% 1990 to 2007•• 55--yr survival 5% in 1970s, 19% since 1999yr survival 5% in 1970s, 19% since 199955 yr survival 5% in 1970s, 19% since 1999yr survival 5% in 1970s, 19% since 1999

JemalJemal, CA Cancer J Clin 61:212CA Cancer J Clin 61:212--236, 2011236, 2011Devesa, Cancer 83:2049Devesa, Cancer 83:2049--53, 199853, 1998

EpidemiologyEpidemiologyp gyp gyEsophageal AdenocarcinomaEsophageal Adenocarcinoma

•• Seattle SEER dataSeattle SEER data•• 5 3 ACA/ 100 000/ year5 3 ACA/ 100 000/ year•• 5.3 ACA/ 100,000/ year5.3 ACA/ 100,000/ year•• 800%800% increase since 1974increase since 1974

•• Utah SEER dataUtah SEER data•• 2.4 ACA/ 100,000/ year2.4 ACA/ 100,000/ year, y, y•• 300%300% increase since 1974increase since 1974

K b C 2002 95 2096 102Kubo, Cancer 2002, 95:2096-102

Esophageal CancerEsophageal Cancerp gp gWorkupWorkup

•• Endoscopic biopsyEndoscopic biopsy•• Endoscopic biopsyEndoscopic biopsy•• CT abdomen and pelvisCT abdomen and pelvis•• If CT negative: EUS for T and N stagingIf CT negative: EUS for T and N staging•• PET: 15% have occult metastatic diseasePET: 15% have occult metastatic disease

Esophageal CancerEsophageal Cancerp gp gTreatment T1aTreatment T1a

•• T1a (lamina propria or muscularisT1a (lamina propria or muscularis•• T1a (lamina propria or muscularis T1a (lamina propria or muscularis mucosae invasion)mucosae invasion)

•• Very low risk of distant mets (<3%)Very low risk of distant mets (<3%)•• Very low risk of distant mets (<3%)Very low risk of distant mets (<3%)•• Very low risk of nodal metsVery low risk of nodal mets•• Endoscopic mucosal resection Endoscopic mucosal resection

without surgery adequatewithout surgery adequate

Esophageal CancerEsophageal Cancerp gp gTreatment T1bTreatment T1b

•• T1b (invades submucosa)T1b (invades submucosa)•• T1b (invades submucosa)T1b (invades submucosa)•• Standard of care is esophagectomyStandard of care is esophagectomy•• NonNon--surgical candidatesurgical candidate

•• 4545 50 Gy + 2 drug chemo50 Gy + 2 drug chemo•• 4545--50 Gy + 2 drug chemo50 Gy + 2 drug chemo•• 60 Gy + 560 Gy + 5--FUFU

Stage I Esophageal CancerStage I Esophageal Cancerg p gg p gPrimary Radiation TherapyPrimary Radiation Therapy

•• 68 stage I esophageal cancer pts68 stage I esophageal cancer pts•• 68 stage I esophageal cancer pts68 stage I esophageal cancer pts•• 18 mucosal18 mucosal•• 50 submucosal50 submucosal

•• EBRT alone: 66 GyEBRT alone: 66 GyEBRT alone: 66 GyEBRT alone: 66 Gy•• EBRT 56EBRT 56--60 Gy + brachy60 Gy + brachy

LDR 5 G 2LDR 5 G 2•• LDR 5 Gy x 2LDR 5 Gy x 2•• HDR 3 Gy x 3HDR 3 Gy x 3

Ishikawa, J Gastro Hepatology 21:1290-1296, 2006

Stage I Esophageal CancerStage I Esophageal Cancerg p gg p gPrimary Radiation TherapyPrimary Radiation Therapy

•• 68 stage I esophageal cancer pts68 stage I esophageal cancer pts•• 68 stage I esophageal cancer pts68 stage I esophageal cancer pts•• 55--yr S 59%yr S 59%•• 55--yr LC 82%yr LC 82%•• 55--yr CSS 80%yr CSS 80%

•• Mucosal 100%Mucosal 100%•• Submucosal 75%Submucosal 75%

•• 2 RT related fistula deaths2 RT related fistula deaths•• 2 RT related fistula deaths2 RT related fistula deathsIshikawa, J Gastro Hepatology 21:1290-1296, 2006

Esophageal Cancer: SurgeryEsophageal Cancer: Surgeryp g g yp g g ySurgical results by stageSurgical results by stage

5 year survival by stage (%)5 year survival by stage (%)y y g ( )y y g ( )

Author Author #pts #pts II IIAIIA IIBIIB IIIIII

W t (UK)W t (UK) 164164 7171 1010Watson (UK)Watson (UK) 164164 7171 1010

Millikan (Rush)Millikan (Rush) 157157 5050 4444 3434 1616O’Rourke (Austral.)O’Rourke (Austral.) 116116 5353 5757 1515Fok (Hong Kong)Fok (Hong Kong) 218218 6666 2828 5050 1414Zhang (Beijing)Zhang (Beijing) 36033603 5858 4545 2727 1313Nakadi (Belgium)Nakadi (Belgium) 101101 9191 5252 1818Nakadi (Belgium)Nakadi (Belgium) 101101 9191 5252 1818Visbal (Mayo)Visbal (Mayo) 220220 9494 3636 1414 1010

Esophageal CancerEsophageal Cancerp gp gGeneral treatment recommendationsGeneral treatment recommendations

•• Squamous cell carcinomaSquamous cell carcinoma•• Squamous cell carcinomaSquamous cell carcinoma•• cT2N0: surgery vs chemoradiationcT2N0: surgery vs chemoradiation•• T3T3--4 or N+: chemoradiation4 or N+: chemoradiation

•• AdenocarcinomaAdenocarcinomaAdenocarcinomaAdenocarcinoma•• cT2N0: surgery vs preop chemoradscT2N0: surgery vs preop chemorads•• T3T3 4 or N+: preop chemoradiation4 or N+: preop chemoradiation•• T3T3--4 or N+: preop chemoradiation4 or N+: preop chemoradiation

•• Stage IV: chemo + RT for dysphagiaStage IV: chemo + RT for dysphagia

Esophageal CancerEsophageal Cancerp gp gMayo surgical resultsMayo surgical results

•• 220 patients: Ivor Lewis resection220 patients: Ivor Lewis resection•• 220 patients: Ivor Lewis resection220 patients: Ivor Lewis resection•• 188 ACA, 31 SQC, 1 leiomyosarcoma188 ACA, 31 SQC, 1 leiomyosarcoma

•• surgical mortality: 1 4%surgical mortality: 1 4%•• surgical mortality: 1.4%surgical mortality: 1.4%•• 5 year overall survival 25%5 year overall survival 25%

•• pTisN0pTisN0 10 pts10 pts 80% 5 yr S80% 5 yr S•• pTisN0pTisN0 10 pts10 pts 80% 5 yr S80% 5 yr S•• pT1N0pT1N0 19 pts19 pts 94% 5 yr S94% 5 yr S•• pT2pT2--3N03N0 38 pts38 pts 36% 5 yr S36% 5 yr SpT2pT2 3N03N0 38 pts38 pts 36% 5 yr S36% 5 yr S•• pT1pT1--2/N+2/N+ 28 pts28 pts 14% 5 yr S14% 5 yr S•• pT3pT3--4N+4N+ 111 pts111 pts 10% 5 yr S10% 5 yr S•• M+M+ 14 pts14 pts 0% 5 yr S0% 5 yr S

Visbal, Ann Thorac Surg 71:1803-8, 2001

Esophageal Cancer: RT + ChemoEsophageal Cancer: RT + Chemop gp gRTOG 8501 SchemaRTOG 8501 Schema

64 Gy / 32 fractions64 Gy / 32 fractions

RR123 pts123 pts108 SQC108 SQC RR

50 Gy in 25 fractions50 Gy in 25 fractions5FU 1 /5FU 1 / 22/d 4 d k 1 5 8 11/d 4 d k 1 5 8 11

108 SQC108 SQC15 ACA15 ACA

5FU, 1 gm/m5FU, 1 gm/m22/day x 4 d weeks 1,5,8,11/day x 4 d weeks 1,5,8,11CDDP, 75 mg/mCDDP, 75 mg/m22 IV bolus weeks 1,5,8,11IV bolus weeks 1,5,8,11

Herskovic, NEJM 326:1593-1598, 1992.

RTOG 8501RTOG 8501

100

Survival by Treatment ArmSurvival by Treatment Arm

80P<0.0001P<0.0001

40

60Alive (%)Alive (%)

RT + chemotherapyRT + chemotherapy

20

40

RT onlyRT only

RT + chemotherapyRT + chemotherapy

00 1 2 3 4 5

RT onlyRT only

Al-Sarraf M et al: JCO 15:283, 1997Al-Sarraf M et al: JCO 15:283, 1997 Years from randomizationYears from randomization

RTOG 8501RTOG 8501

100

Time to Local Failure by Treatment ArmTime to Local Failure by Treatment Arm

80

RT onlyRT onlyRT onlyRT only

40

60% with local disease

% with local disease RT + chemotherapyRT + chemotherapyRT + chemotherapyRT + chemotherapy

RT onlyRT onlyRT onlyRT only

20

40

P=0.05P=0.05

00 1 2 3 4 5

Al-Sarraf M et al: JCO 15:283, 1997Al-Sarraf M et al: JCO 15:283, 1997 Years from randomizationYears from randomization

Esophageal Cancer: RT + ChemoEsophageal Cancer: RT + Chemop gp gRTOG 8501: ToxicityRTOG 8501: Toxicity

Toxicity Toxicity RT + chemoRT + chemo RT aloneRT alone

severesevere 44%44% 25%25%

life threateninglife threatening 20%20% 3%3%f t lf t l 2%2% 0%0%fatalfatal 2%2% 0%0%

Herskovic, NEJM 326:1593-1598, 1992.

T2T2 4 or N+ SQC of esophagus:4 or N+ SQC of esophagus:T2T2--4 or N+ SQC of esophagus:4 or N+ SQC of esophagus:Is routine surgery following Is routine surgery following g y gg y gchemoradiation indicated?chemoradiation indicated?

Esophageal CancerEsophageal Cancerp gp gRT/CT +/RT/CT +/-- Surgery: German StudySurgery: German Study

172 pts172 ptsT3T3 44

FLEPFLEP** ►► 40 Gy+CDDP+ETOP 40 Gy+CDDP+ETOP ►► SurgerySurgery

T3T3--44N0N0--11SQCSQC

RR

FLEP FLEP ►► 65 Gy+CDDP+ETOP65 Gy+CDDP+ETOP

*FLEP = bolus 5*FLEP = bolus 5--FU, leucovorin, etoposide, cisplatinFU, leucovorin, etoposide, cisplatin

Stahl, JCO 23:2310Stahl, JCO 23:2310--17, 200517, 2005

FLEP bolus 5FLEP bolus 5 FU, leucovorin, etoposide, cisplatinFU, leucovorin, etoposide, cisplatin

Survival asSurvival asRandomizedRandomized

Survival ExcludingSurvival ExcludingCrossoversCrossovers

80

100

%)

%)

RandomizedRandomized CrossoversCrossovers

60

80

urvi

val (

%ur

viva

l (%

20

40

atie

nt s

uat

ient

su

SurgerySurgery SurgerySurgery

00 2 4 6 8 10 0 2 4 6 8 10

PP

No surgeryNo surgery No surgeryNo surgery

YearsYears YearsYearsNo overall difference, surgery patients less likely to die of cancer and No overall difference, surgery patients less likely to die of cancer and more likely to die of treatment related complicationsmore likely to die of treatment related complications

Stahl, JCO 23:2310-17, 2005

Locoregional ControlLocoregional Control--German StudyGerman Study100

60

80

%)

%) SurgerySurgery

40

60

Patie

nt (

Patie

nt (

20

PP

No surgeryNo surgery

00 2 4 6 8 10

YearsYearsYearsYearsStahl, JCO 23:2310-17, 2005

FFCD 9102: Phase III Study of ChemoRT FFCD 9102: Phase III Study of ChemoRT vs ChemoRT followed by Surgeryvs ChemoRT followed by Surgery

FFCD 9102: Phase III Study of ChemoRT FFCD 9102: Phase III Study of ChemoRT vs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgery

CTCTDay 1Day 1 Day 22Day 22

A: Surgery days 50-60A: Surgery days 50-60

46 Gy46 GyXRTXRT

g y yg y y

B: ChemoradiationB: ChemoradiationWork-updays 38-41Work-up

days 38-41

20 Gy20 GyDay 43Day 43 Day 64Day 64 Day 92Day 92

yy

CTCTXRTXRT

Day 1Day 1 Day 22Day 22A: Surgery days 50-60A: Surgery days 50-60

B: ChemoradiationB: Chemoradiation15 Gy15 Gy 15 Gy15 Gy

XRTXRT B: ChemoradiationB: ChemoradiationWork-updays 38-41Work-up

days 38-41

15 Gy15 GyDay 43Day 43 Day 64Day 64 Day 92Day 92Bedenne JCO 25:1160-1168, 2007

FFCD 9102: Phase III Study of ChemoRT FFCD 9102: Phase III Study of ChemoRT vs ChemoRT followed by Surgeryvs ChemoRT followed by Surgery

FFCD 9102: Phase III Study of ChemoRT FFCD 9102: Phase III Study of ChemoRT vs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgeryvs ChemoRT followed by Surgery

1.0 A A ( )A A ( )

0.8

Arm A (surgery)Arm A (surgery)Arm B (chemoradiation)Arm B (chemoradiation)

SurvivalSurvival0.6

0.2

0.4

0.00 6 12 18 24 30 36 42 48

Time (months)Time (months)0 6 12 18 24 30 36 42 48

Bedenne JCO 25:1160-1168, 2007

T2T2 4 or N+ ACA of esophagus:4 or N+ ACA of esophagus:T2T2--4 or N+ ACA of esophagus:4 or N+ ACA of esophagus:Surgery vs. Chemoradiation Surgery vs. Chemoradiation g yg y

followed by Surgery?followed by Surgery?

Esophageal Cancer: Preop RT + CTEsophageal Cancer: Preop RT + CTp g pp g pDublin TrialDublin Trial

surgical resection alonesurgical resection alone

113 pts, all ACA113 pts, all ACA

RR

surgical resection alonesurgical resection alone

RR

40 Gy / 15 fractions40 Gy / 15 fractions40 Gy / 15 fractions40 Gy / 15 fractions5FU, 15 mg/kg/day x 5 d, weeks 1,6 surgery5FU, 15 mg/kg/day x 5 d, weeks 1,6 surgeryCDDP, 75 mg/mCDDP, 75 mg/m22 weeks 1,6weeks 1,6

Walsh, NEJM 335:462-467, 1996.

Esophageal Cancer: Preop RT + CTEsophageal Cancer: Preop RT + CTDublin Trial ResultsDublin Trial Results

Esophageal Cancer: Preop RT + CTEsophageal Cancer: Preop RT + CTDublin Trial ResultsDublin Trial ResultsDublin Trial ResultsDublin Trial ResultsDublin Trial ResultsDublin Trial Results

1.0

0.8P=0.01P=0.01

Survival (%)

Survival (%)

0.4

0.6 Multimodal therapy (n=58)Multimodal therapy (n=58)

0.2Surgery alone (n=55)Surgery alone (n=55)

0.00 10 20 30 40 50 60

g y ( )g y ( )

Walsh et al: NEJM 335:465, 1996Walsh et al: NEJM 335:465, 1996

MonthsMonths

Esophageal Cancer: Preop RT + CTEsophageal Cancer: Preop RT + CTp g pp g pDublin Trial ResultsDublin Trial Results

hospitalhospital medianmedian 3 yr3 yr 5 yr5 yrpp yy yytreatmenttreatment mortalitymortality survivalsurvival SS S*S*

surgery alone (55)surgery alone (55) 4%4% 12 mo.12 mo. 6%6% 5%5%surgery alone (55)surgery alone (55) 4%4% 12 mo.12 mo. 6%6% 5%5%

preop RT/CT (58)preop RT/CT (58) 9%9% 17 mo.17 mo. 32%32% 29%29%p = 0.01p = 0.01

*crude survival, all patients followed > 5 yrs*crude survival, all patients followed > 5 yrs

Walsh, NEJM 335:462-467, 1996 and Dis Esophagus 15:121-124, 2002

Esophageal Cancer: Preop RT + CTEsophageal Cancer: Preop RT + CTp g pp g pDublin Trial, Pathologic StageDublin Trial, Pathologic Stage

SurgerySurgery** RT /CT + SRT /CT + STumor stage Tumor stage N = 55N = 55 N = 58N = 58

00 00 13 13 11 22 112a2a 88 18 18 2b2b 22 7733 3838 131333 38 38 13 13 44 55 33

**Expected 5Expected 5--yr survival at Mayo based yr survival at Mayo based on stage distribution: 8%on stage distribution: 8%

Esophageal Cancer: Preop RT + CTEsophageal Cancer: Preop RT + CTp g pp g pCALGB CCALGB C--97819781

500 pts/ 5 yrs500 pts/ 5 yrsSQC or ACASQC or ACAT1T1--3 NxM03 NxM0 RR

surgery alonesurgery alone

ResectableResectableNot more thanNot more than2 cm into cardia2 cm into cardia 55--FU + CDDP + 50.4 GyFU + CDDP + 50.4 Gyyy

followed by surgeryfollowed by surgery

Closed Early (56 pts) due to poor accrualClosed Early (56 pts) due to poor accrualy ( p ) py ( p ) p

CALGB 9781CALGB 9781100 P<0.008P<0.008

60

80

OverallOverall

40

Overallsurvival

(%)

Overallsurvival

(%) TrimodalityTrimodality

20SurgerySurgery

00 1 2 3 4

Years from study entryYears from study entryYears from study entryYears from study entryAdapted from Krasna et al: ASCO GI Symposium, 2006 Original: www.asco.orgAdapted from Krasna et al: ASCO GI Symposium, 2006 Original: www.asco.org

CROSS Phase III trialCROSS Phase III trialPreop CT/RT vs S alonePreop CT/RT vs S alone

Med S 3-yr S

RR

SurgerySurgery 26 mos26 mos 48%48%

363 pts363 ptsRR

41.4 Gy41.4 Gy

T2T2--3N03N0--1186 SQC86 SQC273 ACA273 ACA 41.4 Gy41.4 Gy

CBDCACBDCA SS 49 mos49 mos 59%59%paclitaxelpaclitaxel

A.V. Gaast, ASCO 2010A.V. Gaast, ASCO 2010

cT2cT2 4 or N+ ACA Esophagus:4 or N+ ACA Esophagus:cT2cT2--4 or N+ ACA Esophagus: 4 or N+ ACA Esophagus: CT versus CT/RT followed by CT versus CT/RT followed by yy

surgery?surgery?

Esophageal Cancer: Neoadjuvant ChemoEsophageal Cancer: Neoadjuvant Chemop g jp g jMRCMRC--OE02 OE02

Med SMed S 2 yr S2 yr S

55--FU SurgeryFU Surgery 17 mo17 mo 43%43%

802 pts, resectable802 pts, resectableSQC (247) SQC (247) ACA (533)ACA (533) 55--FU SurgeryFU Surgery 17 mo17 mo 43%43%

CDDPCDDP

RR

( )( )

P 0 004P 0 004

SurgerySurgery 13 5 mo13 5 mo 34%34%

RR P = 0.004P = 0.004

SurgerySurgery 13.5 mo13.5 mo 34%34%

P ti di th ll d (9%) b thP ti di th ll d (9%) b thPreoperative radiotherapy allowed (9%), same on both armsPreoperative radiotherapy allowed (9%), same on both armsMRC Lancet 359:1727-33, 2002

MRCMRC--OE02OE02

80

100

))

60

80

viva

l (%

)vi

val (

%)

20

40

Surv

Surv

CSCS

P 0 004P 0 0040

0 1 2 3 4 5

SSP=0.004P=0.004

YearsYearsPt at risk (events)Pt at risk (events)CSCS 400 (164)400 (164) 231 (73)231 (73) 143 (26)143 (26) 81 (13)81 (13) 36 (2)36 (2) 1414SS 402 (185)402 (185) 212 (76)212 (76) 124 (32)124 (32) 70 (18)70 (18) 28 (5)28 (5) 1010

MRC Lancet 359:1727-33, 2002

SS 402 (185)402 (185) 212 (76)212 (76) 124 (32)124 (32) 70 (18)70 (18) 28 (5)28 (5) 1010

Esophageal CancerEsophageal Cancersop agea Ca cesop agea Ca ceNeoadjuvant Chemo: INT 0113, RTOG 8911Neoadjuvant Chemo: INT 0113, RTOG 8911

PreopPreop**Med SMed S 1 yr S1 yr S 2 yr S2 yr S

467 pts467 pts RRCDDPCDDP55--FUFUx3x3

16.1 mo16.1 mo 62%62% 38%38%

pp RR x3x3

SurgerySurgery 16.8 mo16.8 mo 62%62% 40%40%

*1.5% neutropenic sepsis deaths*1.5% neutropenic sepsis deathsAdditional 2 cycles of chemotherapy postopAdditional 2 cycles of chemotherapy postopKelsen, NEJM339:1979, 1998Additional 2 cycles of chemotherapy postopAdditional 2 cycles of chemotherapy postop

Esophageal CancerEsophageal Cancersop agea Ca cesop agea Ca ceNeoadjuvant Chemo: INT 0113, RTOG 8911Neoadjuvant Chemo: INT 0113, RTOG 8911

PreopPreop**Med SMed S 2 yr S2 yr S LFLF

443 pts443 pts207 SQC207 SQC

CDDPCDDP55--FUFUx3x3RR

16.1 mo16.1 mo 38%38% 27%27%

207 SQC207 SQC236 ACA236 ACA

x3x3

SurgerySurgery

RR

16.8 mo16.8 mo 40%40% 29%*29%*

*1.5% neutropenic sepsis deaths*1.5% neutropenic sepsis deaths*29% LF in R0 41% in R1*29% LF in R0 41% in R1Kelsen, NEJM339:1979, 199829% LF in R0, 41% in R129% LF in R0, 41% in R1

Esophageal CancerEsophageal CancerNeoadjuvant Chemo: INT 0113, RTOG 8911Neoadjuvant Chemo: INT 0113, RTOG 8911

80

100l (

%)

l (%

)Neoadjuvant Chemo: INT 0113, RTOG 8911Neoadjuvant Chemo: INT 0113, RTOG 8911

60

80

surv

ival

surv

ival

20

40

Ove

rall

sO

vera

ll s Surgery (n=234)Surgery (n=234)

00 1 2 3 4 5

OO Chemotherapy plus surgery (n=233)Chemotherapy plus surgery (n=233)

YearsYearsNo. of patients at riskNo. of patients at riskChemotherapy surgeryChemotherapy surgery 136136 7373 4242 2828 1515SurgerySurgery 138138 8181 4545 2727 1616SurgerySurgery 138138 8181 4545 2727 1616

Phase III Study of Preoperative ChemoRT Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinomaor Chemo in GE Junction AdenocarcinomaPhase III Study of Preoperative ChemoRT Phase III Study of Preoperative ChemoRT

or Chemo in GE Junction Adenocarcinomaor Chemo in GE Junction Adenocarcinomaor Chemo in GE Junction Adenocarcinoma or Chemo in GE Junction Adenocarcinoma (POET)(POET)

T3T3--4 GE junction ACA4 GE junction ACA

or Chemo in GE Junction Adenocarcinoma or Chemo in GE Junction Adenocarcinoma (POET)(POET)

T3T3--4 GE junction ACA4 GE junction ACAjjjjArm AArm A

PLF IPLF I PLF IIPLF II PLF III (3 weeks)PLF III (3 weeks) SurgerySurgeryPLF IPLF I PLF IIPLF II PLF III (3 weeks)PLF III (3 weeks) SurgerySurgery

11 66 77 1313 1414 1717 20-2120-21WeekWeek

SurgerySurgery15 x 2 Gy in 3 weeks15 x 2 Gy in 3 weeksPLF IIPLF IIPLF IPLF I

PE (1 week)PE (1 week)

PLF: Cisplatin 50mg/m2, 1h, d 1, 15, 29. Leukovorin/5-FU 500 mg/m2 d 1, 8, 15, 22, 29, 36

PE: Cisplatin 50 mg/m2 1h d 2+8 Etoposide 80 mg/m2 1h d 3-5

PLF: Cisplatin 50mg/m2, 1h, d 1, 15, 29. Leukovorin/5-FU 500 mg/m2 d 1, 8, 15, 22, 29, 36

PE: Cisplatin 50 mg/m2 1h d 2+8 Etoposide 80 mg/m2 1h d 3-5

Arm BArm B

PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5

Stahl, JCO 27:851, 2009JCO 27:851, 2009

Phase III Study of Preoperative ChemoRT or Chemo in Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET)GE Junction Adenocarcinoma (POET)

Phase III Study of Preoperative ChemoRT or Chemo in Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET)GE Junction Adenocarcinoma (POET)( )( )

Overall SurvivalOverall Survival( )( )

Overall SurvivalOverall SurvivalStrataStrata

5FU/CDDP S (2% pCR)5FU/CDDP S (2% pCR)

100

5FU/CDDP S (2% pCR)5FU/CDDP S (2% pCR)

CT CDDP/etop/ 30 Gy/15 S (16% pCR)CT CDDP/etop/ 30 Gy/15 S (16% pCR)

75

Survival Survival

30 Gy/15 S (16% pCR)30 Gy/15 S (16% pCR)

25

50 Arm B (60)Arm B (60)

00 1 2 3 4 5 6

P=0.07P=0.07 Arm A (59)Arm A (59)

0 1 2 3 4 5 6

YearsYearsStahl, JCO 27:851, 2009

Phase III Study of Preoperative ChemoRT or Chemo in Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET)GE Junction Adenocarcinoma (POET)

Phase III Study of Preoperative ChemoRT or Chemo in Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET)GE Junction Adenocarcinoma (POET)( )( )

Freedom from Local Tumor ProgressionFreedom from Local Tumor Progression( )( )

Freedom from Local Tumor ProgressionFreedom from Local Tumor ProgressionStrataStrata

Randomized Arm ARandomized Arm A

100

Censored randomized Arm ACensored randomized Arm ARandomized Arm ARandomized Arm A

Randomized Arm BRandomized Arm BCensored randomized Arm BCensored randomized Arm B

75

SurvivalSurvival

Censored randomized Arm BCensored randomized Arm B

Arm BArm B

25

50Survival

distribution function

Survival distribution

function

Arm BArm B

Arm AArm A

0

25P=0.06P=0.06

0 1 2 3 4 5 6

YearsYearsStahl, JCO 27:851, 2009

Australian MetaAustralian Meta--AnalysisAnalysisChemotherapy vs Surgery AloneChemotherapy vs Surgery AloneChemotherapy vs Surgery AloneChemotherapy vs Surgery Alone

StudyRothStudyRothRothNygaardMaipangSchlag

RothNygaardMaipangSchlagSchlagLawKelsenAncona

SchlagLawKelsenAnconaAnconaMRC

All

AnconaMRC

AllAllAll

0.20.2 0.50.5 11 22 55FavorsFavors FavorsFavors

Val Gebski et al: Lancet Oncol 8:226, 2007Val Gebski et al: Lancet Oncol 8:226, 2007

chemotherapychemotherapyFavors

surgery aloneFavors

surgery alone

CP1320703-2

Australian MetaAustralian Meta--AnalysisAnalysisChemotherapy and RT vs Surgery AloneChemotherapy and RT vs Surgery AloneChemotherapy and RT vs Surgery AloneChemotherapy and RT vs Surgery Alone

StudyNygaardApinop

StudyNygaardApinopp pLePriseBossetUrbaWalsh

p pLePriseBossetUrbaWalshWalshBurmeisterLeeAll (published)

WalshBurmeisterLeeAll (published)

WalshTepperWalshTepper

AllAll

0.20.2 0.50.5 11 22 55FF FF

Val Gebski et al: Lancet Oncol 8:226, 2007Val Gebski et al: Lancet Oncol 8:226, 2007

Favorschemoradiotherapy

Favorschemoradiotherapy

Favorssurgery alone

Favorssurgery alone

CP1320703-1

Australian MetaAustralian Meta--AnalysisAnalysisyy

f ff f•• Hazard ratio for all cause mortality for Hazard ratio for all cause mortality for preoperative chemoRT was 0.81 (preoperative chemoRT was 0.81 (PP = = 0 002)0 002)0.002)0.002)

•• Hazard ratio for all cause mortality forHazard ratio for all cause mortality for•• Hazard ratio for all cause mortality for Hazard ratio for all cause mortality for preoperative chemotherapy was 0.90 (preoperative chemotherapy was 0.90 (PP = = 0 05)0 05)0.05)0.05)

Val Gebski, et al. Lancet Oncol 8:226-34, 2007Val Gebski, et al. Lancet Oncol 8:226-34, 2007

Stage IV Esophageal CancerStage IV Esophageal Cancerg p gg p gDysphagia PalliationDysphagia Palliation

•• RT or CT/RT is preferred over stentRT or CT/RT is preferred over stent•• RT or CT/RT is preferred over stentRT or CT/RT is preferred over stent•• Use small fieldsUse small fields•• 7070--90% dysphagia relief90% dysphagia relief•• 5050--70% dysphagia70% dysphagia--free until deathfree until death•• Transient worsening in 30%Transient worsening in 30%Transient worsening in 30%Transient worsening in 30%

Weight ChartWeight Chartgg

106108110

102104106

Kg Weight

98100

g Weight

9496

0 3 mo 8 mo 11 17 20mo mo mo

Esophageal Cancer:Esophageal Cancer:Esophageal Cancer: Esophageal Cancer: Radiation TechniqueRadiation TechniqueRadiation TechniqueRadiation Technique

Esophageal Cancer Esophageal Cancer p gp gEBRT Dose Escalation, RTOG 94EBRT Dose Escalation, RTOG 94--0505

5FU+CDDP + 5FU+CDDP + 50.4 Gy50.4 Gy / 28/ 28

298 t /4298 t /4

RR298 pts/4 yrs298 pts/4 yrsT1T1--4 NxM04 NxM0SQC or ACASQC or ACAN t ithiN t ithi

5FU+CDDP + 5FU+CDDP + 64.8 Gy64.8 Gy / 36/ 36

No tumor withinNo tumor within2 cm of stomach2 cm of stomach

RT fields = tumor + 5 cm longitudinal marginsRT fields = tumor + 5 cm longitudinal marginsRT fields = tumor + 5 cm longitudinal marginsRT fields = tumor + 5 cm longitudinal margins

Esophageal Cancer Esophageal Cancer EBRT Dose Escalation RTOG 94EBRT Dose Escalation RTOG 94--0505

Esophageal Cancer Esophageal Cancer EBRT Dose Escalation RTOG 94EBRT Dose Escalation RTOG 94--0505

100

EBRT Dose Escalation, RTOG 94EBRT Dose Escalation, RTOG 94--0505EBRT Dose Escalation, RTOG 94EBRT Dose Escalation, RTOG 94--0505

60

80

40

60Alive(%)

Alive(%) 50.4 Gy50.4 Gy

0

20 64.8 Gy64.8 Gy

00 6 12 18 24 30 36

Months from randomizationMonths from randomizationMinsky et al: JCO 20:1167, 2002Minsky et al: JCO 20:1167, 2002

Esophageal CancerEsophageal Cancerp gp gEBRT Dose Escalation, RTOG 94EBRT Dose Escalation, RTOG 94--0505

Med SMed S 2 yr S2 yr S LRFLRF TR deathTR death187 SQC187 SQC31 ACA31 ACA

50.4 Gy50.4 Gy 18 mo18 mo 40%40% 52%52% 2 pts2 pts

RR64.8 Gy64.8 Gy 13 mo13 mo 31%31% 56%56% 11 pts*11 pts*

RR

*7/11 deaths at doses not greater than 50.4 Gy*7/11 deaths at doses not greater than 50.4 Gy

Minsky, JCO 20:1167, 2002Minsky, JCO 20:1167, 2002

Esophageal CancerEsophageal Cancerp gp gTreatment VolumesTreatment Volumes

•• RTOG 8501: 30 Gy to entire esophagusRTOG 8501: 30 Gy to entire esophagus•• RTOG 8501: 30 Gy to entire esophagus, RTOG 8501: 30 Gy to entire esophagus, 20 Gy boost20 Gy boost

•• RTOG 9405: 5 cm longitudinal, 2 cm RTOG 9405: 5 cm longitudinal, 2 cm radial to field edgeradial to field edge

•• Contour GTV (CT, endoscopy report, Contour GTV (CT, endoscopy report, image fusion)image fusion)g )g )

•• CTV: GTV + 3CTV: GTV + 3--4 cm longitudinal, 1 cm 4 cm longitudinal, 1 cm radial expansionradial expansionradial expansionradial expansion

Esophageal Cancer PlanningEsophageal Cancer Planningp g gp g gOAR limitsOAR limits

•• Spinal cord max 45 GySpinal cord max 45 Gy•• Spinal cord max 45 GySpinal cord max 45 Gy•• Lung: V20 < 30%,V10 <40%, V5 < 60%, Lung: V20 < 30%,V10 <40%, V5 < 60%,

mean < 20 Gymean < 20 Gy•• Heart: V30 < 100% V40 < 50%Heart: V30 < 100% V40 < 50%Heart: V30 < 100%, V40 < 50%Heart: V30 < 100%, V40 < 50%•• Liver: mean < 25 Gy, V30< 50%Liver: mean < 25 Gy, V30< 50%•• Kidney: combined V20 < 30%Kidney: combined V20 < 30%

Esophageal Cancer PlanningEsophageal Cancer Planningp g gp g g3D vs. IMRT3D vs. IMRT

•• Lung toxicity with IMRT in trimodalityLung toxicity with IMRT in trimodality•• Lung toxicity with IMRT in trimodality Lung toxicity with IMRT in trimodality patients?patients?

•• MDACC series (2012 GI symposium) MDACC series (2012 GI symposium) •• 208 3D patients208 3D patientspp•• 165 IMRT patients165 IMRT patients•• Less pulmonary complications (ARDS,Less pulmonary complications (ARDS,Less pulmonary complications (ARDS, Less pulmonary complications (ARDS,

effusion, pneumonia, resp. effusion, pneumonia, resp. insufficiency) with IMRTinsufficiency) with IMRTy)y)

Esophageal CancerEsophageal Cancerp gp gFuture DirectionsFuture Directions

•• Individualized therapyIndividualized therapy•• Individualized therapyIndividualized therapy•• RTOG 1010: evaluating trastuzumab in RTOG 1010: evaluating trastuzumab in

HERHER 2+ patients2+ patientsHERHER--2+ patients2+ patients•• CALGB 80803: prediction of response CALGB 80803: prediction of response

ith PETith PETwith PETwith PET•• Organ preservationOrgan preservationg pg p

GASTRIC CANCERGASTRIC CANCERGASTRIC CANCER GASTRIC CANCER Adj ant TherapAdj ant TherapAdjuvant TherapyAdjuvant Therapy

Incidence in United States, 2011Incidence in United States, 2011Carcinoma of the StomachCarcinoma of the Stomach

New CasesNew Cases DeathsDeaths

Any GIAny GI 277,570277,570 139,250139,250yyEsophagusEsophagus 16,98016,980 14,71014,710StomachStomach 21,52021,520 10,34010,340,, ,,

Stomach Ca: >30% death rate decline since 1990Stomach Ca: >30% death rate decline since 1990SiegelSiegel, CA Cancer J Clin 61:212CA Cancer J Clin 61:212--236, 2011236, 2011

Worldwide EpidemiologyWorldwide Epidemiologyp gyp gyCarcinoma of the Stomach Carcinoma of the Stomach

•• 989,600 new cases in 2008989,600 new cases in 2008•• 738,000 deaths738,000 deaths•• 8% of total cancers 10% of deaths8% of total cancers 10% of deaths•• 8% of total cancers, 10% of deaths8% of total cancers, 10% of deaths•• Substantial decrease in most of the Substantial decrease in most of the

worldworld


Gastric CancerGastric CancerIndications for Radiation TherapyIndications for Radiation Therapy

•• Penetration through muscularis propriaPenetration through muscularis propria•• Penetration through muscularis propria Penetration through muscularis propria (T3(T3--4 or posterior wall T2)4 or posterior wall T2)

•• Regional lymph node involvementRegional lymph node involvement

Patterns of FailurePatterns of FailureUniversity of Minnesota Reoperative SeriesUniversity of Minnesota Reoperative Series

•• 107 patients with gastric cancer107 patients with gastric cancer•• 107 patients with gastric cancer107 patients with gastric cancer•• 68 patients 2nd look laparotomy68 patients 2nd look laparotomy•• 39 patients symptomatic 2nd look39 patients symptomatic 2nd look

P ttP tt O lO l C tC tPatternPattern OnlyOnly ComponentComponent

LRFLRF 29%29% 88%88%LRFLRF 29%29% 88%88%PSPS 4%4% 54%54%DMDM 6%6% 29%29%

Gunderson, IJROBP 8:1-11, 1982

Mayo Adjuvant CTMayo Adjuvant CT--RT TrialRT Trialy jy jGastric CancerGastric Cancer

62 t d t 196562 t d t 1965 1974197462 resected pts, 196562 resected pts, 1965--19741974(pre rand)(pre rand)81% node +81% node +

5 year survival5 year survivalAllAll Exclude 10Exclude 10** As treatedAs treated

RR4%4% 4%4% 12%12%ObservationObservation

3750 G /243750 G /24P < 0.05P < 0.05

23%23% 21%21% 21%21%3750 cGy/243750 cGy/2455--FU 15 mg/kg x 3dFU 15 mg/kg x 3d

*10 refused RT, 3/10 survived 5 years*10 refused RT, 3/10 survived 5 yearsMoertel, JCO, 1984

Gastric Cancer Adjuvant TherapyGastric Cancer Adjuvant Therapyj pyj pyIntergroup 0116Intergroup 0116

T3T3--4 and/or N+4 and/or N+Complete resectionComplete resection85% node +85% node +

ObservationObservation603 pts 603 pts

RR55 FUFU 45 Gy45 Gy 55 FUFU55--FUFU 45 Gy45 Gy 55--FUFUCFCF 55--FUFU CFCFx1x1 CFCF x 2x 2

Macdonald, NEJM 345:725, 2001

Intergroup Gastric Adjuvant StudyS i l

Intergroup Gastric Adjuvant StudyS i lSurvivalSurvival

100

80

40

60Survival

(%)Survival

(%)Chemo-RT 3 yr S 50%Chemo-RT 3 yr S 50%

20Surgery only 3 yr S 41%Surgery only 3 yr S 41%P=0 005P=0 005

00 24 48 72 96 120

Surgery only 3 yr S 41%Surgery only 3 yr S 41%P=0.005P=0.005

NEJM 345:725, 2001NEJM 345:725, 2001 Months after registrationMonths after registration

Gastric Surgical Intergroup TrialR l P tt

Gastric Surgical Intergroup TrialR l P ttRelapse PatternsRelapse Patterns

50 ObservationObservation

40

Obse at oRadiochemotherapyObse at oRadiochemotherapy

46%46%

30%%

27%27%

10

20 27%27%

19%19%

12%12% 13%13%

0Local Regional Distant

7%7%12%12%

Local Regional DistantCourtesy of S. SmalleyCourtesy of S. Smalley

Gastric Cancer Adjuvant TherapyGastric Cancer Adjuvant Therapyj pyj pyIntergroup 0116 CriticismsIntergroup 0116 Criticisms

•• Radiation made up for bad surgeryRadiation made up for bad surgery•• Radiation made up for bad surgeryRadiation made up for bad surgery•• No D2 dissection mandatedNo D2 dissection mandated•• No D1 dissection in many ptsNo D1 dissection in many pts

•• No need for radiationNo need for radiation –– perioperativeperioperativeNo need for radiation No need for radiation perioperative perioperative chemotherapy is adequatechemotherapy is adequate

Surgical Quality ControlSurgical Quality Controlg yg yGastric Adjuvant Intergroup 0116Gastric Adjuvant Intergroup 0116

•• D2 dissection recommended but not mandatedD2 dissection recommended but not mandated•• D2 dissection recommended but not mandatedD2 dissection recommended but not mandated•• Surgical checklist, operative note and Surgical checklist, operative note and

pathology report utilizedpathology report utilizedpathology report utilizedpathology report utilized

DD N PtN Pt M d SM d SDD No. PtsNo. Pts Med SMed S

D0D0 299 (54%)299 (54%) 27 mo27 moD0D0 299 (54%)299 (54%) 27 mo27 moD1D1 198 (36%)198 (36%) 29 mo29 moD2D2 54 (10%)54 (10%) 48 mo48 mo

P = NSP = NS

Hundahl, Annals of Surgical Oncology 9:278-286, 2002

Gastric CancerGastric CancerLymph Node StationsLymph Node Stations

L tL t 1 3 51 3 5 N1N1•• Lesser curvatureLesser curvature 1,3,51,3,5 N1N1•• Greater curvatureGreater curvature 2,4,62,4,6 N1N1•• Left gastricLeft gastric 77 N2N2•• Left gastricLeft gastric 77 N2N2•• Common hepaticCommon hepatic 88 N2N2•• CeliacCeliac 99 N2N2CeliacCeliac 99 N2N2•• SplenicSplenic 10,1110,11 N2N2•• Extraregional Extraregional 1212--1616 N3,N4N3,N4gg

Maruyama European J Cancer 34:1480 1489 1998Maruyama, European J Cancer 34:1480-1489, 1998

Gastric CancerGastric CancerBritish D2 resection studyBritish D2 resection study

737 patients, 337 advanced disease737 patients, 337 advanced disease400 eligible400 eligible96% followed > 3 yrs96% followed > 3 yrs 5 i l5 i l96% followed > 3 yrs96% followed > 3 yrs 5 yr survival5 yr survival

D1D1 35%35%RR

D1D1 35%35%

D2D2 33%33%D2D2 33%33%

Cuschieri, Br J Cancer 79:1522-30, 1999

MRC D1 vs D2 Resection TrialS r i al

MRC D1 vs D2 Resection TrialS r i alSurvivalSurvival

100

80

40

60Survival

(%)Survival

(%)

D1 resectionD1 resection

20

40D2 resectionD2 resection

00 1 2 3 4 5 6 7

Br J Cancer 79:1522, 1999Br J Cancer 79:1522, 1999YearsYears

MRC D1 vs D2 Resection TrialMRC D1 vs D2 Resection TrialMorbidity and MortalityMorbidity and Mortality

O t D1 D2 PO t D1 D2 PResectionResection

Outcome D1 D2 P

H it l t lit (%) 6 5 13 0 04

Outcome D1 D2 P

H it l t lit (%) 6 5 13 0 04Hospital mortality (%) 6.5 13 0.04Hospital mortality (%) 6.5 13 0.04

Postop morbidity (%) 28 46 <0.001Postop morbidity (%) 28 46 <0.001

Lancet 347:995, 1996Lancet 347:995, 1996

Gastric CancerGastric CancerDutch D2 resection studyDutch D2 resection study

1989 1989 -- 19931993996 pts entered996 pts entered711 curative resection711 curative resection711 curative resection711 curative resection

Comp.Comp. PO DeathPO Death 5 yr S5 yr S RelapseRelapse

RRD1D1 25%25% 4%4% 45%45% 43%43%

D2D2 43%43% 10%10% 47%47% 37%37%

Bonenkamp, N Engl J Med 340:908-14, 1999

Dutch D1 vs D2 Resection Trial inPatients with Gastric Cancer

Dutch D1 vs D2 Resection Trial inPatients with Gastric CancerPatients with Gastric Cancer

SurvivalPatients with Gastric Cancer

Survival100

80D1D2D1D2

Survival(%)

Survival(%)

40

60 Curative resectionsCurative resections

20

40

All eligible ptAll eligible pt

00 1 2 3 4 5 6 7 8

NEJM 340:908, 1999Hartgrink JCO 22:2069-77,2005NEJM 340:908, 1999Hartgrink JCO 22:2069-77,2005 Years after surgeryYears after surgery

Dutch D1 vs D2 Resection TrialSurvival in Patients with R0 Resection, Excluding

Dutch D1 vs D2 Resection TrialSurvival in Patients with R0 Resection, ExcludingSurvival in Patients with R0 Resection, Excluding

Hospital Deaths*Survival in Patients with R0 Resection, Excluding

Hospital Deaths*100

80D1D2D1D2

Patients(%)

Patients(%)

40

60 SurvivalSurvival

20

40Risk of relapseRisk of relapse

00 1 2 3 4 5 6 7 8

NEJM 340:908, 1999* Increased operative mortality, complications, reoperation in D2 armNEJM 340:908, 1999* Increased operative mortality, complications, reoperation in D2 arm

Years after surgeryYears after surgery

Dutch D1 vs D2 Resection TrialDutch D1 vs D2 Resection Trial

80

100

al (%

)al

(%)

60

80

surv

iva

surv

iva

20

40

Ove

rall

Ove

rall D2D2

D1D1P=0 34P=0 340

0 2.5 5 7.5 10 12.5 15

OO P=0.34P=0.34

Years after randomizationYears after randomizationNo. at riskNo. at riskD1D1 380380 231231 174174 149149 132132 108108 4747D2D2 331331 191191 158158 138138 125125 110110 7070

Songun: Lancet Oncology 11:439-49, 2010

Dutch D1 vs D2 Resection TrialDutch D1 vs D2 Resection Trial

80

100

val (

%)

val (

%)

P=0.31P=0.31 P=0.10P=0.10

%)

%)

60

80

e su

rviv

e su

rviv

D1D1

rren

ce (%

rren

ce (%

20

40

ease

ease

--fre

fre

D1D1

D2D2 D2D2

Rec

urR

ecur

00 2.5 5 7.5 10 12.5 15

Dis

eD

ise

Years after randomizationYears after randomization0 2.5 5 7.5 10 12.5 15

Years after randomizationYears after randomizationYears after randomizationYears after randomization

380380 218218 168168 144144 130130 100100 4747331331 185185 152152 136136 123123 109109 7171

No. at riskNo. at riskD1D1D2D2

Years after randomizationYears after randomization

380380 215215 168168 144144 141141 110110 9696331331 185185 152152 133133 124124 109109 9292


Surgical Quality ControlSurgical Quality Controlg yg yMaruyama IndexMaruyama Index

•• Based on 3843 Japanese patientBased on 3843 Japanese patient•• Based on 3843 Japanese patient Based on 3843 Japanese patient database, all had D2 resectionsdatabase, all had D2 resections

•• risk of nodal involvement at each of 16 risk of nodal involvement at each of 16 stations based on: age, sex, Borrmann stations based on: age, sex, Borrmann t t i l ti d tht t i l ti d thtype, tumor size, location, depth, type, tumor size, location, depth, histologyhistology

•• Index predicts likelihood of involved Index predicts likelihood of involved nodes in undissected nodal groupsnodes in undissected nodal groups


Intergroup 0116 Survival by MIIntergroup 0116 Survival by MI

80

100

MI<5MI<5 6565 2727 NRNRNo.No. EventsEvents

MedianMedianin monthsin months

60

80MIMI≥≥55MI<5MI<5

4914916565

3153152727

2727NRNR

40%%

P=0.005P=0.005

0

20

00 20 40 60 80 100 120

Months after registrationMonths after registration

Hundahl: Annals of Surgical Oncology 9:278-286, 2002

Gastric CancerGastric CancerAdjuvant Therapy Adjuvant Therapy -- Intergroup 0116Intergroup 0116

•• Multivariate analysisMultivariate analysis•• pathologic variables: T and N stagepathologic variables: T and N stagep g gp g g•• surgical variables: type of surgical variables: type of

gastrectomy, D level, Maruyamagastrectomy, D level, Maruyamagastrectomy, D level, Maruyama gastrectomy, D level, Maruyama indexindex

•• No evidence of differing effect ofNo evidence of differing effect of•• No evidence of differing effect of No evidence of differing effect of adjuvant therapy in any subgroupadjuvant therapy in any subgroup


Gastric CancerGastric CancerDutch D2 resection studyDutch D2 resection study

GroupGroup 55--yr Syr S 55--yr Syr S 55--yr Syr ST3T3 N+N+ AllAll

Dutch D1Dutch D1 16%16% 26%26%Dutch D2Dutch D2 22%22% 30%30%Dutch D2Dutch D2 22%22% 30%30%

0116 S0116 S ~26%~26%0116 S RT/CT0116 S RT/CT 44%44%0116 S + RT/CT0116 S + RT/CT ~44%~44%

Macdonald NEJM 345:725 2001Bonenkamp, N Engl J Med 340:908-14, 1999Macdonald, NEJM 345:725, 2001

Gastric Cancer Gastric Cancer -- Adjuvant ChemoAdjuvant ChemojjMAGIC Trial (MRC ST02)MAGIC Trial (MRC ST02)

503 pts503 ptsCurativeCurative

5 yr OS 5 yr OS resectionresection

503 pts503 ptsACA stomachACA stomachEG junctionEG junctionlower esophaguslower esophagus

ECF S ECF S ECF ECF x3x3 x3x3

36%36% 69%69%p gp g

RR

Surgery aloneSurgery alone 23%23% 66%66%Surgery aloneSurgery alone 23%23% 66%66%

OS HR 0.75, P = 0.009OS HR 0.75, P = 0.009

Cunningham, N Engl J Med 355:11-20, 2006

MAGIC Trial SurvivalMAGIC Trial Survival

0.8

1.0iv

aliv

al

0 4

0.6

all s

urv

all s

urv

PerioperativePerioperativechemotherapychemotherapy

0.2

0.4

Ove

raO

vera

Surgery aloneSurgery aloneP=0.009P=0.0090.0

0 12 24 36 48 60 72MonthsMonthsMonthsMonths

No. at riskNo. at riskPerioperativePerioperative 250250 168168 111111 7979 5252 3838 2727chemotherapychemotherapySurgerySurgery 253253 155155 8080 5050 3131 1818 99

MRC Lancet 359:1727-33, 2002

SurgerySurgery 253253 155155 8080 5050 3131 1818 99

Dutch Gastric Ca Group StudyDutch Gastric Ca Group Study1.0

yy Overall survival of eligible Overall survival of eligible ti t ( 56)ti t ( 56)

0.6

0.8

obab

ility

obab

ility

P=0.17P=0.17

patients (n=56)patients (n=56)

0.4

0.6

viva

l pro

viva

l pro

SurgerySurgery

0 0

0.2

Surv

Surv FAMTXFAMTX

0.00 24 48 72 96 120

Months since randomizationMonths since randomization

Hartgrink: Eur J Surg Oncol 30:643-9, 2004

Gastric Cancer Gastric Cancer -- Adjuvant ChemoAdjuvant Chemo--RTRTjjCALGB 80801CALGB 80801

546 pts546 ptsMedian 3Median 3--yr 3yr 3--yr yr Survival OS DFSSurvival OS DFS

546 pts546 ptsACA stomachACA stomachEG junctionEG junction

5FU/LV5FU/LV 5FU/RT5FU/RT 5FU/LV5FU/LV 37 mos37 mos 50%50% 46%46%

RR

ECFECF 55--FU/RTFU/RT ECFECF 38 mos38 mos 52%52% 47%47%ECFECF 55 FU/RTFU/RT ECFECF 38 mos38 mos 52%52% 47%47%

P = 0.80P = 0.80

Fuchs, JCO 29:15s, 4003, 2011

Gastric Cancer Gastric Cancer -- Adjuvant ChemoAdjuvant ChemojjMetaMeta--metameta--analysisanalysis

AuthorAuthor YrYr # trials# trials OROR 95% conf95% conf

JJ ** 20022002 2121 0 840 84 0 740 74 0 960 96JanungerJanunger** 20022002 2121 0.840.84 0.74 0.74 -- 0.960.96HuHu 20022002 1414 0.560.56 0.40 0.40 -- 0.790.79PanziniPanzini 20022002 1717 0.720.72 0.620.62 -- 0.840.84PanziniPanzini 20022002 1717 0.720.72 0.62 0.62 0.840.84MariMari 20002000 2020 0.820.82 0.75 0.75 -- 0.890.89EarleEarle**** 19991999 1313 0.800.80 0.66 0.66 -- 0.970.97HH 19931993 1111 0 880 88 0 780 78 1 081 08HermansHermans 19931993 1111 0.880.88 0.78 0.78 -- 1.081.08

*Wh A i t i l l d d OR 0 90 (0 83*Wh A i t i l l d d OR 0 90 (0 83 1 12)1 12)*When Asian trials excluded, OR = 0.90 (0.83 *When Asian trials excluded, OR = 0.90 (0.83 -- 1.12)1.12)**Asian trials excluded**Asian trials excluded

Gastric Cancer Adjuvant TherapyGastric Cancer Adjuvant Therapyj pyj pyMAGIC and 0116MAGIC and 0116

S aloneS alone CMTCMTS aloneS alone CMTCMT5 yr survival5 yr survival01160116 26%26% 44%44%01160116 26%26% 44%44%MAGICMAGIC 23%23% 36%36%

Local relapseLocal relapse01160116 19%19% 7%7%01160116 19%19% 7%7%MAGICMAGIC** 21%21% 14%14%

*24% of patients who died had LR prior to death*24% of patients who died had LR prior to death

Gastric Adjuvant TherapyGastric Adjuvant Therapyj pyj pyCRITICS trial CRITICS trial –– DCCG,GOFDCCG,GOF

ECC x 3 ECC x 3 D1+surgery D1+surgery ECC x 3ECC x 3g yg y

RRIbIb--IVaIVaGastriGastricc

ECC x 3 ECC x 3 D1+ surgery D1+ surgery CT/RTCT/RT

ccGEJGEJ788 788 ptsptsptspts

ECC: Epirubicin 50mg/m2, CDDP 60 mg/m2, capecitabine 1000 mg/m2 bidECC: Epirubicin 50mg/m2, CDDP 60 mg/m2, capecitabine 1000 mg/m2 bid

CT/RT: 45 Gy in 25 fractions + capecitabine 575 mg/m2 bidCT/RT: 45 Gy in 25 fractions + capecitabine 575 mg/m2 bidCT/RT: 45 Gy in 25 fractions capecitabine 575 mg/m2 bidCT/RT: 45 Gy in 25 fractions capecitabine 575 mg/m2 bid

Gastric Adjuvant TherapyGastric Adjuvant Therapyj pyj pyARTIST trial ARTIST trial –– 한국한국

CP x 6CP x 6

RRIbIb--IVaIVaD2 D2 GastriGastri

CP x 2 CP x 2 CT/RT CT/RT CP x 2CP x 2

GastriGastricc458 458 ptsptsptspts20042004--88CP: Capecitabine 1000 mg/m2 bid, CDDP 60 mg/m2CP: Capecitabine 1000 mg/m2 bid, CDDP 60 mg/m2

CT/RT: 45 Gy in 25 fractions + capecitabine 825 mg/m2 bidCT/RT: 45 Gy in 25 fractions + capecitabine 825 mg/m2 bidCT/RT: 45 Gy in 25 fractions capecitabine 825 mg/m2 bidCT/RT: 45 Gy in 25 fractions capecitabine 825 mg/m2 bid

1.0llGastric Adjuvant Gastric Adjuvant ––Artist TrialArtist Trial

0.8

1.0su

rviv

asu

rviv

a

XPXP

0.4

0.6

sese--fr

ee s

free

s

XP/XRT/XPXP/XRT/XPAll ptsAll pts

0 0

0.2

Dis

eas

Dis

eas

P=0.0862P=0.0862

0.00 12 24 36 48 60 72

MonthsMonthso t so t sTreatmentTreatment No.No. EventEvent 1212 2424 3636 4848 6060

(no.)(no.)XP/XRT/XPXP/XRT/XP 230230 5555 2121 4444 4949 5353 5555XPXP 228228 7272 1515 3939 4646 6767 7070

Lee: JCO 30:268-273, 2012

XPXP 228228 7272 1515 3939 4646 6767 7070

1.0llGastric Adjuvant Gastric Adjuvant ––Artist TrialArtist Trial

0.8

1.0su

rviv

asu

rviv

a

XPXP

0.4

0.6

sese--fr

ee s

free

s

XP/XRT/XPXP/XRT/XPNode + pts

0 0

0.2

Dis

eas

Dis

eas

P=0.0365P=0.0365

0.00 12 24 36 48 60 72

MonthsMonthso t so t sTreatmentTreatment No.No. EventEvent 1212 2424 3636 4848 6060

(no.)(no.)XP/XRT/XPXP/XRT/XP 203203 4949 1919 4242 4545 4747 4949XPXP 193193 6666 1414 3737 5151 6262 6565

Lee: JCO 30:268-273, 2012

XPXP 193193 6666 1414 3737 5151 6262 6565

Gastric Cancer: RadiationGastric Cancer: RadiationGastric Cancer: Radiation Gastric Cancer: Radiation TechniqueTechniqueTechniqueTechnique

Impact of Site of Primary Lesion and TN Stage Impact of Site of Primary Lesion and TN Stage Irradiation Treatment Volumes Irradiation Treatment Volumes -- EG JunctionEG Junction

Remaining Remaining Tumor Bed Tumor Bed TN StageTN Stage Stomach Stomach Volumes* Volumes* Nodal VolumesNodal Volumes

T3N0; postT3N0; post Dependent Dependent Medial L hemiMedial L hemi-- None or perigastric None or perigastric wall T2N0 wall T2N0 on surgon surg--path path diaphragm, adj diaphragm, adj ±± periesophageal† periesophageal†

findings**findings** body of pancreasbody of pancreasfindings findings body of pancreasbody of pancreasT4N0 T4N0 Dependent Dependent As for T3N0 plus As for T3N0 plus Nodes related to Nodes related to

on surgon surg--path path site(s) of adherence site(s) of adherence site of adherence; site of adherence; findings** findings** with 3with 3--5 cm margin 5 cm margin perigastric, periesophperigastric, periesoph

T1T1--2N+2N+ PreferablePreferable Not indicated for T1 Not indicated for T1 Periesoph, mediast, Periesoph, mediast, perigastric, celiacperigastric, celiac

T3T3--4N+4N+ Preferable Preferable As for T3, T4N0As for T3, T4N0 As for T1As for T1--2N+ 2N+ and T4N0and T4N0

* * Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT)Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT)**Optional if >5 cm surg/path margins and substantial increased morbidity risk **Optional if >5 cm surg/path margins and substantial increased morbidity risk p g p g yp g p g y† † Optional if D1+D2 resection and Optional if D1+D2 resection and ≥≥15 nodes examined by pathologist15 nodes examined by pathologist

Impact of Site of Primary Lesion and TN Stage Impact of Site of Primary Lesion and TN Stage Irradiation Treatment Volumes Irradiation Treatment Volumes -- Cardia/Proximal 1/3 StomachCardia/Proximal 1/3 Stomach

Remaining Remaining Tumor Bed Tumor Bed TN StageTN Stage StomachStomach Volumes*Volumes* Nodal VolumesNodal VolumesT3N0; postT3N0; post DependentDependent Medial L hemiMedial L hemi-- None or perigastricNone or perigastricT3N0; postT3N0; post DependentDependent Medial L hemiMedial L hemi None or perigastricNone or perigastricwall T2N0wall T2N0 on surgon surg--pathpath diaphragm, bodydiaphragm, body

findings**findings** of pancreas (of pancreas (±± tail)tail)

T4N0T4N0 Prefer but Prefer but As for T3N0 plus As for T3N0 plus Nodes related to site of Nodes related to site of depends ondepends on site(s) of adherencesite(s) of adherence adherence adherence ±± perigastric,perigastric,surgsurg--path**path** with 3with 3--5 cm margin5 cm margin celiac, periesoph, mediastceliac, periesoph, mediast

T1T1--2N+2N+ PreferablePreferable Not indicated for T1Not indicated for T1 Perigastric, celiac, splenic, Perigastric, celiac, splenic, suprapanc, suprapanc, ±± periesoph, periesoph, pancpanc-- duod†, portaduod†, porta--hepatis†hepatis†

T3T3--4N+4N+ PreferablePreferable As for T3, T4N0As for T3, T4N0 As for T1As for T1--2N+ and T4N02N+ and T4N0

**Use preop imaging (CT barium swallow) surgical clips and postop imaging (CT)Use preop imaging (CT barium swallow) surgical clips and postop imaging (CT)Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT)Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT)**Optional if >5 cm surg/path margins and substantial increased morbidity risk **Optional if >5 cm surg/path margins and substantial increased morbidity risk

††Optional if D1 + D2 resection and 15 nodes examined by pathologistOptional if D1 + D2 resection and 15 nodes examined by pathologist

Impact of Site of Primary Lesion and TN Stage Impact of Site of Primary Lesion and TN Stage Irradiation Treatment Volumes Irradiation Treatment Volumes -- Body/Middle 1/3 StomachBody/Middle 1/3 Stomach


T3N0; postT3N0; post YesYes Body of pancreasBody of pancreas None or perigastric None or perigastric wall T2N0wall T2N0 ((±± tail)tail)

T4N0T4N0 YesYes As for T3N0 plusAs for T3N0 plus Nodes related toNodes related toT4N0T4N0 YesYes As for T3N0 plusAs for T3N0 plus Nodes related toNodes related tosites(s) of adherencesites(s) of adherence site of adherencesite of adherence

T1T1--2N+2N+ YesYes Not indicated for T1 Not indicated for T1 Perigastric, celiac, Perigastric, celiac, suprapanc splenicsuprapanc splenicsuprapanc, splenic, suprapanc, splenic, pancpanc--duod, portaduod, porta--hepatitishepatitis

T3T3--4N+4N+ YesYes As for T3 T4N0As for T3 T4N0 As for T1As for T1--2N+ and2N+ andT3T3--4N+4N+ YesYes As for T3, T4N0As for T3, T4N0 As for T1As for T1--2N+ and 2N+ and T4N0T4N0

**Use preop imaging (CT barium swallow) surgical clips and postop imaging (CT barium swallow)Use preop imaging (CT barium swallow) surgical clips and postop imaging (CT barium swallow)Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT, barium swallow)Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT, barium swallow)

Impact of Site of Primary Lesion and TN Stage Impact of Site of Primary Lesion and TN Stage EBRT Treatment Volumes EBRT Treatment Volumes -- Antrum/Pylorus/Distal 1/3 StomachAntrum/Pylorus/Distal 1/3 Stomach


T3N0; postT3N0; post Dependent Dependent Head of pancreasHead of pancreas None or perigastric None or perigastric wall T2N0 wall T2N0 on surgon surg--path**path** ((±± body)body)

T4N0 T4N0 Prefer but Prefer but As for T3N0 plusAs for T3N0 plus Nodes related to site(s) Nodes related to site(s) depends ondepends on site(s) of adherencesite(s) of adherence of adherence of adherence ±±surgsurg--path**path** with 3with 3--5 cm margin5 cm margin perigastric, pancperigastric, panc--duodduod

T1T1--2N+ 2N+ Preferable Preferable Not indicated for T1 Not indicated for T1 Perigastric, pancPerigastric, panc--duod, duod, portaporta--hepatitis celiachepatitis celiacportaporta--hepatitis, celiac, hepatitis, celiac, suprapanc; optsuprapanc; opt--spl hilum† spl hilum†

T3T3--4N+ 4N+ PreferablePreferable As for T3, T4N0As for T3, T4N0 As for T1As for T1--2N+ and T4N02N+ and T4N0

**Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT) Use preop imaging (CT, barium swallow), surgical clips and postop imaging (CT) **Optional if >5 cm surg/path margins and substantial increased morbidity risk **Optional if >5 cm surg/path margins and substantial increased morbidity risk ††Exclude if D1 + D2 dissection with Exclude if D1 + D2 dissection with ≥≥15 nodes examined and only 115 nodes examined and only 1--2 N+2 N+

Optimized Irradiation Fields Optimized Irradiation Fields –– GastricGastricAntral PrimaryAntral Primary T3N1T3N1Antral Primary Antral Primary –– T3N1T3N1

•• Tumor bed:Tumor bed: Head of pancreas 1st and 2ndHead of pancreas 1st and 2nd•• Tumor bed:Tumor bed: Head of pancreas,1st and 2nd Head of pancreas,1st and 2nd part of duodenumpart of duodenum

•• Nodal volumes:Nodal volumes: Perigastric, pancPerigastric, panc--duod, duod, portaporta--hepatis, celiac, suprahepatis, celiac, supra--panc; panc;

ti lti l l i hill i hiloptional optional -- splenic hilumsplenic hilum•• Gastric remnant:Gastric remnant: To be includedTo be included•• Tolerance organs/structures:Tolerance organs/structures: Kidneys, Kidneys,

liver spinal cordliver spinal cordliver, spinal cordliver, spinal cord

Gastric Cancer PlanningGastric Cancer PlanningggOAR limitsOAR limits

•• Spinal cord max 45 GySpinal cord max 45 Gy•• Spinal cord max 45 GySpinal cord max 45 Gy•• Lung: V20 < 20%Lung: V20 < 20%•• Heart: V40<30%Heart: V40<30%•• Liver: mean < 25 Gy, V30< 50%Liver: mean < 25 Gy, V30< 50%•• Kidney: combined V20 < 30%Kidney: combined V20 < 30%Kidney: combined V20 < 30%Kidney: combined V20 < 30%•• Small bowel: V45 < 150 cc, V30 < 300 ccSmall bowel: V45 < 150 cc, V30 < 300 cc

Kidneys

Liver

SmallBowel

GE Junction Cancer: PostGE Junction Cancer: Post--op RTop RTGE Junction Cancer: PostGE Junction Cancer: Post--op RTop RT

PANCREATIC PANCREATIC CANCERCANCER

Locally AdvancedLocally AdvancedSurgical Adjuvant TherapySurgical Adjuvant Therapy

Incidence in United States, 2011Incidence in United States, 2011Carcinoma of the PancreasCarcinoma of the Pancreas

New CasesNew Cases DeathsDeaths

Any GIAny GI 277,570277,570 139,250139,250yyPancreasPancreas 44,03044,030 37,66037,660

Pancreas Ca: #4 cause of death in both sexesPancreas Ca: #4 cause of death in both sexes

SiegelSiegel, CA Cancer J Clin 61:212CA Cancer J Clin 61:212--236, 2011236, 2011

Worldwide EpidemiologyWorldwide Epidemiologyp gyp gyCarcinoma of the PancreasCarcinoma of the Pancreas

•• 266,000 deaths worldwide in 2008 266,000 deaths worldwide in 2008 •• Developed countriesDeveloped countries

•• 165,100 new cases in 2008165,100 new cases in 2008,,•• 161,800 deaths in 2008161,800 deaths in 2008


Major BreakthroughsMajor Breakthroughsj gj gPancreatic AdenocarcinomaPancreatic Adenocarcinoma

1. 1935: Whipple describes 1. 1935: Whipple describes pancreaticoduodenectomypancreaticoduodenectomypancreaticoduodenectomy pancreaticoduodenectomy

2. 1965: Childs and Moertel report 2. 1965: Childs and Moertel report i d i l ith RT/5i d i l ith RT/5 FUFUimproved survival with RT/5improved survival with RT/5--FU FU

3. 1997: Burris reports 13. 1997: Burris reports 1--yr survival of yr survival of pp yy18% with gemcitabine vs. 2% 518% with gemcitabine vs. 2% 5--FU FU

4 2011: FOLFIRINOX4 2011: FOLFIRINOX4. 2011: FOLFIRINOX4. 2011: FOLFIRINOX

Pancreatic CancerPancreatic Cancer

••Unresectable DiseaseUnresectable Disease••Unresectable DiseaseUnresectable Disease••Surgical Adjuvant TherapySurgical Adjuvant Therapy••Surgical Adjuvant TherapySurgical Adjuvant Therapy

Locally Advanced Locally Advanced P ti CP ti CPancreatic Cancer: Pancreatic Cancer:

Chemotherapy alone?Chemotherapy alone?Chemotherapy alone?Chemotherapy alone?

Pancreas AdenocarcinomaPancreas AdenocarcinomaL ll Ad d & M t t ti DiL ll Ad d & M t t ti DiLocally Advanced & Metastatic DiseaseLocally Advanced & Metastatic Disease

100

80P=0.0025P=0.0025

40

60GEMGEM5-FU5-FU

Survival(%)

Survival(%)

20

M thM th

00 2 4 6 8 10 12 14 16 18 20

MonthsMonthsAdapted from: Burris: JCO 15:2403, 1997Adapted from: Burris: JCO 15:2403, 1997

CALGB 80303 Trial DesignCALGB 80303 Trial Design

RA GemcitabineGemcitabine

BevacizumabBevacizumabGemcitabineGemcitabineBevacizumabBevacizumab

Advanced Advanced pancreaticpancreatic

cancercancer

Advanced Advanced pancreaticpancreatic

cancercancer

NDO

BevacizumabBevacizumabBevacizumabBevacizumab

cancercancern=590n=590cancercancern=590n=590 M

IZ

GemcitabineGemcitabinePlaceboPlaceboGemcitabineGemcitabinePlaceboPlacebo

EPlaceboPlaceboPlaceboPlacebo

StratificationStratificationStratification• Performance status: 0/1 vs 2• Extent of disease: metastatic vs locally advanced

Stratification• Performance status: 0/1 vs 2• Extent of disease: metastatic vs locally advanced

Kinder et al: ASCO, 2007Kinder et al: ASCO, 2007

• Prior radiation: yes/no• Prior radiation: yes/no

CP1282739-129

CALGB 80303CALGB 80303P i F S i l b T t t AP i F S i l b T t t A

1.0

Progression-Free Survival by Treatment ArmProgression-Free Survival by Treatment Arm

0.8 Bevacizumab 4.9 moBevacizumab 4.9 mo

0.4

0.6Proportionsurviving

Proportionsurviving

Pl b 4 7Pl b 4 70.2

P=0.99P=0.99

Placebo 4.7 moPlacebo 4.7 mo

0.00 5 10 15 20 25 30

M th f t d tM th f t d tMonths from study entryMonths from study entry

Kindler et al: ASCO, 2007Kindler et al: ASCO, 2007

Metastatic Pancreas ACAMetastatic Pancreas ACAACCORD4/PRODIGE11ACCORD4/PRODIGE11

•• 342 PS 0342 PS 0 1 metastatic pancreas ca pts1 metastatic pancreas ca pts•• 342 PS 0342 PS 0--1 metastatic pancreas ca pts1 metastatic pancreas ca pts•• 59% body and tail primary59% body and tail primary•• 14% biliary stent14% biliary stent•• Randomized to:Randomized to:

•• Gemcitabine x 6 mosGemcitabine x 6 mos•• FOLFIRINOX x 6 mosFOLFIRINOX x 6 mos

C NEJM 2011 364 1817 25Conroy, NEJM 2011; 364:1817-25

Overall SurvivalOverall Survival-- ACCORD4/PRODIGE11ACCORD4/PRODIGE11

80

100

%)

%) Hazard ratio 0.57 (95% CI 0.45Hazard ratio 0.57 (95% CI 0.45--0.73)0.73)

P<0.001 by stratified logP<0.001 by stratified log--rank testrank test

60

80

abili

ty (%

abili

ty (%

FolfirinoxFolfirinox

y gy g

20

40

Prob

aPr

oba

G it biG it bi0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

GemcitabineGemcitabine

MonthsMonthsNo. at riskNo. at riskGemcitabineGemcitabine 171171 134134 8989 4848 2828 1414 77 66 33 33 22 22 22 22 11FOLFIRINOXFOLFIRINOX 171171 146146116116 8181 6262 3434 2020 1313 99 55 33 22 22 22 22

Conroy: NEJM 2011; 364:1817-25

O OO O 66 66 88 66 33 00 33 99 55 33

Locally Advanced Locally Advanced yyPancreatic Cancer: Pancreatic Cancer:

Ch di tiCh di tiChemoradiationChemoradiation

Pancreas AdenocarcinomaPancreas AdenocarcinomaL ll Ad d DiL ll Ad d DiLocally Advanced DiseaseLocally Advanced Disease

64 patients64 patients64 patients64 patients64 patients64 patientsUnresectable pancreas ACAUnresectable pancreas ACA64 patients64 patientsUnresectable pancreas ACAUnresectable pancreas ACA

Mean SMean SMean SMean S

3535--40 Gy + saline40 Gy + saline3535--40 Gy + saline40 Gy + saline

P<0 05P<0 05P<0 05P<0 05

6.3 mo6.3 mo6.3 mo6.3 mo

RRRR P<0.05P<0.05P<0.05P<0.05

3535--40 Gy + 40 Gy + 3535--40 Gy + 40 Gy + 10.4 mo10.4 mo10.4 mo10.4 mo

RRRR

RT fields not specifiedRT fields not specified

yy55--FU, 15 mg/kg x 3FU, 15 mg/kg x 3

yy55--FU, 15 mg/kg x 3FU, 15 mg/kg x 3

RT fields not specifiedMoertel, Lancet 2:865, 1969RT fields not specifiedMoertel, Lancet 2:865, 1969


1.0

0.85-FU + EBRT (32 patients)5-FU + EBRT (32 patients)

Probability of survival

(%)

Probability of survival

(%) 0.4

0.6 P<0.05P<0.05

( )( )

0.2 EBRT + saline (32 patients)

EBRT + saline (32 patients)

M thM th

0.00 5 10 15 20

Adapted from: Moertel and Colleagues: Lancet 2:865, 1969Adapted from: Moertel and Colleagues: Lancet 2:865, 1969MonthsMonths

Pancreas AdenocarcinomaPancreas AdenocarcinomaU t bl GITSG #1U t bl GITSG #1Unresectable: GITSG #1Unresectable: GITSG #1

194 patients194 patients194 patients194 patients Med SMed SMed SMed S 11--yr Syr S11--yr Syr SppUnresectable pancreas ACAUnresectable pancreas ACA

ppUnresectable pancreas ACAUnresectable pancreas ACA

60 G60 G60 G60 G

Med SMed S(wk)(wk)

Med SMed S(wk)(wk)

23232323

11--yr Syr S(%)(%)

11--yr Syr S(%)(%)

1010101060 Gy60 Gy60 Gy60 Gy

RRRR 40 Gy + 540 Gy + 5--FUFU40 Gy + 540 Gy + 5--FUFU

23232323

31313131

10101010

33333333P<0.05P<0.05P<0.05P<0.05

60 Gy + 560 Gy + 5--FUFU60 Gy + 560 Gy + 5--FUFU

RRRR yyyy

39393939 40404040RT: Split course in 20 Gy increments; initial 40 Gy was to “entire pancreas”, final 20 Gy to tumor3 days bolus 5-FU with each course, then weekly

RT: Split course in 20 Gy increments; initial 40 Gy was to “entire pancreas”, final 20 Gy to tumor3 days bolus 5-FU with each course, then weekly

Int J Rad Oncol Biol Phys 5:1643, 1979Cancer 48:1705, 1981Int J Rad Oncol Biol Phys 5:1643, 1979Cancer 48:1705, 1981

Pancreas AdenocarcinomaPancreas AdenocarcinomaU t bl GITSG #1U t bl GITSG #1

1.0

Unresectable: GITSG #1Unresectable: GITSG #1

0.8 60 Gy + 5-FU60 Gy + 5-FU

0.4

0.6SurvivalSurvival

0.2 60 Gy60 Gy40 Gy + 5-FU40 Gy + 5-FU

0.00 20 40 60 80 100

W kW kAdapted from: Cancer 48:1705, 1981Adapted from: Cancer 48:1705, 1981 WeeksWeeks

Chemoradiation versus Chemoradiation versus Chemotherapy alone?Chemotherapy alone?

Chemoradiation for Ca PancreasChemoradiation for Ca PancreasCommon Sense RationaleCommon Sense Rationale

•• Chemotherapy is relatively ineffective forChemotherapy is relatively ineffective for•• Chemotherapy is relatively ineffective for Chemotherapy is relatively ineffective for pancreatic cancerpancreatic cancer

•• Chemotherapy alone not curative for any Chemotherapy alone not curative for any GI malignancyGI malignancy

•• If local disease is not controlled, If local disease is not controlled, metastatic disease cannot be controlledmetastatic disease cannot be controlled

•• Local disease is symptomaticLocal disease is symptomatic

Pancreas AdenocarcinomaPancreas AdenocarcinomaU t bl ECOGU t bl ECOGUnresectable: ECOG

(Stomach Cancer Included)Unresectable: ECOG

(Stomach Cancer Included)

40 Gy +40 Gy +40 Gy +40 Gy +Med SMed S(mo)(mo)

Med SMed S(mo)(mo)yy

55--FU, 600 x 3,FU, 600 x 3,then 600 weeklythen 600 weekly

yy55--FU, 600 x 3,FU, 600 x 3,then 600 weeklythen 600 weekly 8.28.28.28.2

55 FU 600 weeklyFU 600 weekly55 FU 600 weeklyFU 600 weekly 8 38 38 38 3

RRRR55--FU, 600 weeklyFU, 600 weekly55--FU, 600 weeklyFU, 600 weekly 8.38.38.38.3

22% f ti t ll d t li ibl bl ith RT i 10%22% f ti t ll d t li ibl bl ith RT i 10%

RT field: “…smallest size that could reasonably encompass the tumor.”RT field: “…smallest size that could reasonably encompass the tumor.”RT field: “…smallest size that could reasonably encompass the tumor.”RT field: “…smallest size that could reasonably encompass the tumor.”

22% of patients cancelled or not eligible, problem with RT in 10%Klaassen: JCO 3:373, 198522% of patients cancelled or not eligible, problem with RT in 10%Klaassen: JCO 3:373, 1985

Pancreas AdenocarcinomaPancreas AdenocarcinomaU t bl ECOGU t bl ECOGUnresectable: ECOGUnresectable: ECOG

1.0

0.8RT (40 Gy) + 5-FURT (40 Gy) + 5-FU

SurvivalSurvival0.4

0.6( y)( y)

5 FU alone5 FU alone P=NSP=NS

0.2

5-FU alone5-FU alone P NSP NS

M thM th

0.00 5 10 15 20 25

Adapted from: Klaassen: JCO 3:373, 1985Adapted from: Klaassen: JCO 3:373, 1985 MonthsMonths

Pancreas AdenocarcinomaPancreas AdenocarcinomaU t bl GITSG #3U t bl GITSG #3Unresectable: GITSG #3Unresectable: GITSG #3

43 patients43 patients43 patients43 patients Med SMed SMed SMed S 11--yr Syr S11--yr Syr SppUnresectable pancreas ACAUnresectable pancreas ACA

ppUnresectable pancreas ACAUnresectable pancreas ACA

SMF 2SMF 2SMF 2SMF 2

Med SMed S(wk)(wk)

Med SMed S(wk)(wk)

32323232

11--yr Syr S(%)(%)

11--yr Syr S(%)(%)

19191919SMF x 2 yrSMF x 2 yrSMF x 2 yrSMF x 2 yr

RRRR32323232 19191919

P<0.02P<0.02P<0.02P<0.02

54 Gy +54 Gy +55 FU (350 x 3) x 2FU (350 x 3) x 254 Gy +54 Gy +55 FU (350 x 3) x 2FU (350 x 3) x 2

RRRR42424242 41414141

55--FU (350 x 3) x 2FU (350 x 3) x 2+ SMF+ SMF55--FU (350 x 3) x 2FU (350 x 3) x 2+ SMF+ SMF

RT fields not specifiedRT fields not specifiedGITSG: JNCI 80:751, 1988GITSG: JNCI 80:751, 1988

RT fields not specifiedRT fields not specified

Pancreas AdenocarcinomaPancreas AdenocarcinomaU t bl GITSG #3U t bl GITSG #3

100

Unresectable: GITSG #3Unresectable: GITSG #3

80

SMF + RTSMF + RT

40

60Survival

(%)Survival

(%)

SMF + RTSMF + RTSMFSMF

20

00 20 40 60 80 100

W kW kWeeksWeeksAdapted from: GITSG: JNCI 80:751, 1988Adapted from: GITSG: JNCI 80:751, 1988

Pancreas AdenocarcinomaPancreas AdenocarcinomaF h St dF h St d

119 patients119 patients119 patients119 patients

French StudyFrench Study

119 patients119 patients119 patients119 patients

ChemoRT (60 Gy in 30 fractions,ChemoRT (60 Gy in 30 fractions,CIFU, CDDP) CIFU, CDDP) GemGemChemoRT (60 Gy in 30 fractions,ChemoRT (60 Gy in 30 fractions,CIFU, CDDP) CIFU, CDDP) GemGem

RRRRGemcitabineGemcitabineGemcitabineGemcitabine

RRRR

12% on RT arm no RT, only 42% at least 75% of RT/CT dose12% on RT arm no RT, only 42% at least 75% of RT/CT dose

Chauffert, Annals of Oncology, May 2008Chauffert, Annals of Oncology, May 2008

Pancreas AdenocarcinomaPancreas AdenocarcinomaF h St dF h St d

11--yearyear11--yearyear

French StudyFrench Study

11 yearyearsurvivalsurvival

(%)(%)

11 yearyearsurvivalsurvival

(%)(%)

ChemoRTChemoRTChemoRTChemoRT 32323232

GemcitabineGemcitabineGemcitabineGemcitabine 53535353

RRRRGemcitabineGemcitabineGemcitabineGemcitabine 53535353

Chauffert, Annals of Oncology, May 2008Chauffert, Annals of Oncology, May 2008

Pancreas CancerPancreas CancerU t bl F h St dU t bl F h St dUnresectable: French StudyUnresectable: French Study

100

80GemcitabineGemcitabine

P=0.057P=0.057

Survival(%)

Survival(%) 40

60

ChemoRTChemoRT

20

M thM th

00 6 12 18 24 30 36

MonthsMonthsAdapted from Chauffert et al: ASCO, 2006Adapted from Chauffert et al: ASCO, 2006

CP1282739-146

Locally Advanced Pancreatic ACALocally Advanced Pancreatic ACAyyECOG E4201ECOG E4201

MedianMedianMedianMedianMedianMediansurvivalsurvival

(mo)(mo)

MedianMediansurvivalsurvival

(mo)(mo)

RT + GemRT + Gem 11.111.1RT + GemRT + Gem 11.111.1

G it biG it bi 9 29 2G it biG it bi 9 29 2

RRRR P = 0.17P = 0.17

GemcitabineGemcitabine 9.29.2GemcitabineGemcitabine 9.29.2

Loehrer, J Clin Oncol 29:4105Loehrer, J Clin Oncol 29:4105--4112, 20114112, 2011

Locally Advanced Pancreatic ACALocally Advanced Pancreatic ACAECOG E4201ECOG E4201ECOG E4201ECOG E4201

0 8

1.0

al

al Total no.Total no.

of Patientsof Patients DeadDead AliveAlive MeanMean

0.6

0.8

surv

iva

surv

iva

abili

ty)

abili

ty) GEMGEM 3737 3737 00 9.29.2

GEM + RTGEM + RT 3434 3434 00 11.111.1

0.2

0.4

Ove

rall

Ove

rall

(pro

b a(p

roba

0.0

0.2

0 3 6 9 12 15 18 21 24 27 30 33 36

OO P=0.34P=0.34

0 3 6 9 12 15 18 21 24 27 30 33 36

SurvivalSurvivalGEM aloneGEM alone 7676 3232 1111 55 00GEM plus RTGEM plus RT 7676 5050 2929 1212 66

MonthsMonths


GEM plus RTGEM plus RT 7676 5050 2929 1212 66

Unresectable Pancreatic CancerUnresectable Pancreatic CancerSummarySummary

1-yr survivalStudy Treatment RT/CT CTStudy Treatment RT/CT CTMayo 40 Gy + 5-FU 25%GTSG 1 40 Gy + 5-FU 33%GTSG 1 60 G + 5 FU 40%GTSG 1 60 Gy + 5-FU 40%GTSG 2 60 Gy + 5-FU 35%GTSG 3 54 Gy + 5-FU 41%yGTSG 3 SMF 19%ECOG 40 Gy + 5-FU 28% 28%NCCTG 50 4 Gy + CDDP/Gem 40%NCCTG 50.4 Gy + CDDP/Gem 40%French 60 Gy + 5-FU/CDDP 32%French Gem 53%E 4201 Gem +/-50.4 Gy 50% 32%

Chemoradiation: Are there Chemoradiation: Are there benefits beyond extended benefits beyond extended

i l ti ?i l ti ?survival time?survival time?

Pancreas CancerPancreas CancerL ll Ad d Di T i i St dL ll Ad d Di T i i St dLocally Advanced Disease: Taipei StudyLocally Advanced Disease: Taipei Study

34 patients34 patients34 patients34 patients34 patients34 patientsUnresectable pancreas ACAUnresectable pancreas ACA34 patients34 patientsUnresectable pancreas ACAUnresectable pancreas ACA


RT + gemRT + gemRT + gemRT + gem

P<0 027P<0 027P<0 027P<0 027

14.5 mo14.5 mo14.5 mo14.5 mo

RRRR P<0.027P<0.027P<0.027P<0.027

RT + bolus 5FURT + bolus 5FURT + bolus 5FURT + bolus 5FU 7.1 mo7.1 mo7.1 mo7.1 mo

RRRR

RT: 50 4 to 61 2 Gy at 1 8 per day; 45 Gy to tumor and nodes then boostRT: 50 4 to 61 2 Gy at 1 8 per day; 45 Gy to tumor and nodes then boostRT: 50.4 to 61.2 Gy at 1.8 per day; 45 Gy to tumor and nodes, then boostChung-Pin et al: Int J Rad Oncol Biol Phys 57:98-104, 2003RT: 50.4 to 61.2 Gy at 1.8 per day; 45 Gy to tumor and nodes, then boostChung-Pin et al: Int J Rad Oncol Biol Phys 57:98-104, 2003

Pancreas CancerPancreas CancerL ll Ad d Di T i i St dL ll Ad d Di T i i St d

100

Locally Advanced Disease: Taipei StudyLocally Advanced Disease: Taipei Study

80

100

RT + GEMRT + GEM

40

60Survival(%)

Survival(%)

20

40( )( )

RT + 5-FURT + 5-FU

00 3 6 9 12 15 18 21 24 27 30 33

P=0.027P=0.027

Time (months)Time (months)Adapted from Chung-Pin et al: Int J Rad Oncol Biol Phys 57:98-104, 2003Adapted from Chung-Pin et al: Int J Rad Oncol Biol Phys 57:98-104, 2003

Pancreas CancerPancreas CancerL ll Ad d Di T i i St dL ll Ad d Di T i i St dLocally Advanced Disease: Taipei StudyLocally Advanced Disease: Taipei Study

•• Better pain control with GemcitabineBetter pain control with Gemcitabine•• Better pain control with GemcitabineBetter pain control with Gemcitabine

•• Higher average monthly KPS with Higher average monthly KPS with GemcitabineGemcitabine

•• Higher average monthly KPS with Higher average monthly KPS with GemcitabineGemcitabineGemcitabineGemcitabine

Si ifi tl lit dj t dSi ifi tl lit dj t d

GemcitabineGemcitabine

Si ifi tl lit dj t dSi ifi tl lit dj t d•• Significantly more quality adjusted Significantly more quality adjusted months with Gemcitabinemonths with Gemcitabine

•• Significantly more quality adjusted Significantly more quality adjusted months with Gemcitabinemonths with Gemcitabine

Pancreas CancerPancreas CancerLocally Advanced Disease:Locally Advanced Disease:Locally Advanced Disease:

Kagoshima University Study (Japan)Locally Advanced Disease:

Kagoshima University Study (Japan)

34 patients34 patientsUnresectable pancreas ACAUnresectable pancreas ACA34 patients34 patientsUnresectable pancreas ACAUnresectable pancreas ACA

Mean SMean SMean SMean S 1 Yr S1 Yr S1 Yr S1 Yr S

ObservationObservationObservationObservation


6.4 mo6.4 mo6.4 mo6.4 mo

1 Yr S1 Yr S1 Yr S1 Yr S

0.0%0.0%0.0%0.0%

RRRR P=0.0009P=0.0009P=0.0009P=0.0009

RT: 50 4 Gy in 28 fractions in most patients including tumor and regional nodesRT: 50 4 Gy in 28 fractions in most patients including tumor and regional nodes

RT + PVI 5FURT + PVI 5FURT + PVI 5FURT + PVI 5FU 13.2 mo13.2 mo13.2 mo13.2 mo 53.3%53.3%53.3%53.3%

RT: 50.4 Gy in 28 fractions in most patients, including tumor and regional nodesShinchi et al: Int J Rad Oncol Biol Phys 53:146-150, 2002RT: 50.4 Gy in 28 fractions in most patients, including tumor and regional nodesShinchi et al: Int J Rad Oncol Biol Phys 53:146-150, 2002




80

100

Chemoradiation (n=16)

Chemoradiation (n=16)

60Survival(%)

Survival(%) No therapyNo therapy

(n=16)(n=16)

20

40(%)(%) No therapy

(n=15)No therapy

(n=15)

00 2 4 6 8 10 12 14 16 18

P=0.0009P=0.0009

0 2 4 6 8 10 12 14 16 18Months after diagnosisMonths after diagnosis

Adapted from Shinchi et al: Int J Rad Oncol Biol Phys 53:146-150, 2002Adapted from Shinchi et al: Int J Rad Oncol Biol Phys 53:146-150, 2002




• Better average KPS with RT and continuous infusion 5FU

• Better average KPS with RT and continuous infusion 5FU

• Number of hospital days per month of survival was better (fewer) with RT and

• Number of hospital days per month of survival was better (fewer) with RT andsurvival was better (fewer) with RT and more continuous infusion 5FU

• 80% of patients in the active treatment

survival was better (fewer) with RT and more continuous infusion 5FU

• 80% of patients in the active treatment• 80% of patients in the active treatment group experienced pain relief, with a median duration of pain relief of

• 80% of patients in the active treatment group experienced pain relief, with a median duration of pain relief of p5.2 months

p5.2 months


100 Overall Survival (n=47)Overall Survival (n=47)80

Overall Survival (n=47)Overall Survival (n=47)

40

60Survival(%)

Survival(%)

20 Median survival 10.2 moMedian survival 10.2 mo

M thM th

00 6 12 18

MonthsMonthsAdapted from: Haddock, JCO 25:2567-2572, 2007

Pancreas CancerPancreas CancerNCCTG Ph II St dNCCTG Ph II St dNCCTG Phase II StudyNCCTG Phase II Study

Overall improvement in Overall improvement in symptom distress score 4.7±14.1 P=0.06symptom distress score 4.7±14.1 P=0.06

Haddock et al: JCO, June 2007Haddock et al: JCO, June 2007

Pancreas CancerPancreas CancerL ll Ad d DiL ll Ad d Di

Mean ± stdMean ± std

Locally Advanced DiseaseLocally Advanced Disease

Mean ± std(last QOL –

QoL subscale baseline; n=33) P


QoL subscale baseline; n=33) P)

Appetite 8.3±26.3 0.07

)

Appetite 8.3±26.3 0.07

Insomnia 12.9±3.01 0.03

Frequency of pain 21 2±26 6 <0 001

Insomnia 12.9±3.01 0.03

Frequency of pain 21 2±26 6 <0 001Frequency of pain 21.2±26.6 <0.001

Outlook 16.7±30.4 <0.01

Frequency of pain 21.2±26.6 <0.001

Outlook 16.7±30.4 <0.01Haddock et al: JCO, June 2007Haddock et al: JCO, June 2007

Pancreas CancerPancreas CancerL ll Ad d DiL ll Ad d DiLocally Advanced DiseaseLocally Advanced Disease

Mean ± stdMean ± stdMean ± std(last QOL –

QoL subscale baseline; n=33) P


QoL subscale baseline; n=33) P)

Frequency 12.7±30.0 0.02f i

)

Frequency 12.7±30.0 0.02f iof pain

Severity 10 6±31 8 0 06

of pain

Severity 10 6±31 8 0 06Severity 10.6±31.8 0.06of painSeverity 10.6±31.8 0.06of pain

Haddock: Linear Analogue Self-Assessment. JCO, 2007Haddock: Linear Analogue Self-Assessment. JCO, 2007

Pancreatic CancerPancreatic Cancer

••Unresectable DiseaseUnresectable Disease••Unresectable DiseaseUnresectable Disease••Surgical Adjuvant TherapySurgical Adjuvant Therapy••Surgical Adjuvant TherapySurgical Adjuvant Therapy

Important Clinical TrialsImportant Clinical Trialspp

•• GITSGGITSG C 1987 59 2006C 1987 59 2006 20102010•• GITSGGITSG Cancer 1987;59:2006Cancer 1987;59:2006--20102010

•• EORTCEORTC JH Klinkenbijl, Ann Surg 1999;230:776JH Klinkenbijl, Ann Surg 1999;230:776--8484

•• RTOG 9704RTOG 9704 WF Regine, JAMA 2008;299:1019WF Regine, JAMA 2008;299:1019--10261026

•• ESPACESPAC--11 Neoptolemos: Lancet 2001;358:1576-85, Neoptolemos: NEJM 2004;350:1200-10

•• CONKOCONKO--001001 H Oetttle, JAMA 2007;297:267H Oetttle, JAMA 2007;297:267--277277

Pancreas Cancer Adjuvant TherapyPancreas Cancer Adjuvant TherapyGITSG Ph III T i lGITSG Ph III T i l

100

GITSG Phase III TrialGITSG Phase III Trial

80 Chemotherapy + radiotherapyChemotherapy + radiotherapy

40

60Survival(%)

Survival(%) P=0.03P=0.03

20ControlControl

00 6 12 18 24 30 36 42 48 54 60

M thM thMonthsMonthsAdapted from: Arch Surg 120:899, 1985Adapted from: Arch Surg 120:899, 1985

Pancreas Cancer Adjuvant TherapyPancreas Cancer Adjuvant TherapyEORTC Ph III T i lEORTC Ph III T i l

100

EORTC Phase III TrialEORTC Phase III Trial

P=0 099 (2 sided)P=0 099 (2 sided)

60

80

S i lS i l

P=0.099 (2 sided)< 0.05 if one sided test usedP=0.099 (2 sided)< 0.05 if one sided test used

40

60Survival(%)

Survival(%)

Chemo RTChemo RT

0

20ObservationObservation

0 1 2 3 4 5 6 7 8YearsYears

Adapted from: Ann Surg 244:332, 2006Adapted from: Ann Surg 244:332, 2006

Pancreas AdenocarcinomaPancreas AdenocarcinomaSurgical Adjuvant TherapySurgical Adjuvant Therapy

Med SMed S 2 yr S2 yr S 5 yr S5 yr S40 Gy split40 Gy split2222 21 mo21 mo 43%43% 14%14%

11 mo11 mo 18%18% 5%5%GITSGGITSG**

40 Gy split40 Gy splitbolus 5 FUbolus 5 FUobservationobservation

RR2121

2222

17 mo17 mo 37%37% 20%20%40 Gy split40 Gy splitbolus 5 FUbolus 5 FU

5858

EORTCEORTC13 mo13 mo 23%23% 10%10%

bolus 5 FUbolus 5 FUobservationobservation

RR6161

*Weekly 5*Weekly 5--FU x 2 yr in GITSG trial, no maintenance chemo in EORTC FU x 2 yr in GITSG trial, no maintenance chemo in EORTC Cancer 59:2006, 1987.Cancer 59:2006, 1987.

Pancreas Cancer Adjuvant TherapyPancreas Cancer Adjuvant TherapyESPAC 1 T i lESPAC 1 T i lESPAC-1 TrialESPAC-1 Trial

• 61 centers in 11 countries

• 40 Gy split course + bolus 5-FU

• 61 centers in 11 countries

• 40 Gy split course + bolus 5-FUy p

• RT fields, technique: Not specified, no central audit

y p

• RT fields, technique: Not specified, no central auditcentral audit

• Chemo = 6 cycles 5-FU/CF

central audit

• Chemo = 6 cycles 5-FU/CF

S i l Adj t ThS i l Adj t ThPancreas AdenocarcinomaPancreas Adenocarcinoma

2/942/94 5/975/972/942/94 5/975/97

Surgical Adjuvant TherapySurgical Adjuvant Therapy

ESPACESPAC--1 Study1 StudyESPACESPAC--1 Study1 Study2/942/94--5/975/97541541/289 patients/289 patients6161/53 centers/53 centers

2/942/94--5/975/97541541/289 patients/289 patients6161/53 centers/53 centers

ESPACESPAC 1 Study1 StudyESPACESPAC 1 Study1 Study

40 Gy split + 540 Gy split + 5--FUFU40 Gy split + 540 Gy split + 5--FUFU11 countries11 countries11 countries11 countries

RRRR

y py py py p

55--FU + CF x 6FU + CF x 655--FU + CF x 6FU + CF x 6RRRR

40 Gy split + 540 Gy split + 5--FU FU →→ 55--FU/CF x 6FU/CF x 640 Gy split + 540 Gy split + 5--FU FU →→ 55--FU/CF x 6FU/CF x 6

Neoptolemos: Lancet 358:1576 2001Neoptolemos: Lancet 358:1576 2001

ObservationObservationObservationObservationNeoptolemos: Lancet 358:1576, 2001Neoptolemos: NEJM 350:1200, 2004Neoptolemos: Lancet 358:1576, 2001Neoptolemos: NEJM 350:1200, 2004

Pancreas Cancer: ESPAC-1 TrialPancreas Cancer: ESPAC-1 TrialS i l Ch di th NS i l Ch di th NSurvival – Chemoradiotherapy vs NoneSurvival – Chemoradiotherapy vs None

100

80 P=0.05P=0.05

40

60Survival(%)

Survival(%) No ChemoradiotherapyNo Chemoradiotherapy

20ChemoradiotherapyChemoradiotherapy

M thM th

00 12 24 36 48 60 72

ChemoradiotherapyChemoradiotherapy

MonthsMonthsAdapted from: Neoptolemos et al: NEJM 350:1204, 2004Adapted from: Neoptolemos et al: NEJM 350:1204, 2004

Pancreas Cancer: ESPAC-1 TrialPancreas Cancer: ESPAC-1 TrialS i l Ch th NS i l Ch th NSurvival – Chemotherapy vs NoneSurvival – Chemotherapy vs None

100

80P=0.009P=0.009

40

60Survival(%)

Survival(%) Adjuvant chemoAdjuvant chemo

20No adjuvant chemoNo adjuvant chemo

M thM th

00 12 24 36 48 60 72

MonthsMonthsAdapted from: Neoptolemos et al: NEJM 350:1204, 2004Adapted from: Neoptolemos et al: NEJM 350:1204, 2004

S i l S S + CT RTS i l S S + CT RTPancreas Ductal CancerPancreas Ductal Cancer

Survival: Surgery vs. Surgery + CT-RTSurvival: Surgery vs. Surgery + CT-RT

Observation Chemo-RTObservation Chemo-RTPt Median 5 yr Pt Med. 5 yr

Series (no.) (mo) (%) (no.) (mo) (%)Pt Median 5 yr Pt Med. 5 yr

Series (no.) (mo) (%) (no.) (mo) (%)GTSG 22 11 5 21 20 19EORTC 54 13 10 60 17 20GTSG 22 11 5 21 20 19EORTC 54 13 10 60 17 20ESPAC-1 69 17 11 145 14-20 7-13ESPAC-1 69 17 11 145 14-20 7-13

Pancreas AdenocarcinomaPancreas AdenocarcinomaCONKO 001 P t ti Adj t St dCONKO 001 P t ti Adj t St d

368 patients resected pancreas368 patients resected pancreas368 patients resected pancreas368 patients resected pancreas

CONKO-001 Postoperative Adjuvant StudyCONKO-001 Postoperative Adjuvant Study

368 patients resected pancreas 368 patients resected pancreas cancer patientscancer patients368 patients resected pancreas 368 patients resected pancreas cancer patientscancer patients

5-yr SObservationObservation 5%5%ObservationObservation 5%5%

RRRR P= 0 005

GemcitabineGemcitabine 21%21%GemcitabineGemcitabine 21%21%

RRRR P= 0.005

%%%%

Oettle and Colleagues: JAMA 297:267, 2007Oettle and Colleagues: JAMA 297:267, 2007

Pancreas AdenocarcinomaPancreas AdenocarcinomaCONKO 001 P t ti Adj t St dCONKO 001 P t ti Adj t St d

100

CONKO-001 Postoperative Adjuvant StudyCONKO-001 Postoperative Adjuvant StudyOverall SurvivalOverall Survival

80 P=0.005P=0.005

40

60Cumulative%

Cumulative% GemcitabineGemcitabine

20ObservationObservation

00 12 24 36 48 60 72 84 96

M thM thAdapted from: Oettle and Colleagues: JAMA 297:267, 2007Adapted from: Oettle and Colleagues: JAMA 297:267, 2007

MonthsMonths

Pancreas CancerPancreas CancerLocoregional relapseLocoregional relapse

L l R l F ll i SL l R l F ll i SLocal Relapse Following SurgeryLocal Relapse Following SurgeryStudyStudy # pts# pts % + margins% + margins LRLRGITSGGITSG 2222 00 33%33%GITSGGITSG 2222 00 33%33%EORTCEORTC 103103 19%19% 36%36%CONKOCONKO--001001 182182 19%19% 41%41%

Local Relapse Following Surgery + chemotherapyLocal Relapse Following Surgery + chemotherapyStudyStudy # pts# pts % + margins% + margins LRLRyy pp ggESPACESPAC--11 289289 18%18% 34%34%**CONKOCONKO--001001 182182 19%19% 34%34%

*63% of relapse pts had local component

Pancreas AdenocarcinomaPancreas AdenocarcinomaS i l Adj t ThS i l Adj t Th

RTOG 97RTOG 97--0404: Closed July 2002: Closed July 2002RTOG 97RTOG 97--0404: Closed July 2002: Closed July 2002

Surgical Adjuvant TherapySurgical Adjuvant Therapy330 patients330 patients330 patients330 patientsRTOG 97RTOG 97 0404: Closed July 2002: Closed July 2002RTOG 97RTOG 97 0404: Closed July 2002: Closed July 20025 years5 years5 years5 years

Potentially curative resectionPotentially curative resectionPotentially curative resectionPotentially curative resection

PVIPVI55--FUFUPVIPVI55--FUFU

RRRRRTRTPVI 5PVI 5--FUFURTRTPVI 5PVI 5--FUFU

PVIPVI55--FUFUPVIPVI55--FUFU

WeeklyWeeklyWeeklyWeekly

RRRRRTRTRTRT WeeklyWeeklyWeeklyWeeklyyy

GemGemyy

GemGem PVI 5PVI 5--FUFUPVI 5PVI 5--FUFUyy

GemGemyy

GemGem

Chemo duration is 3 wk pre-RT and 12 wk post-RTChemo duration is 3 wk pre-RT and 12 wk post-RTChemo duration is 3 wk pre-RT and 12 wk post-RTChemo duration is 3 wk pre-RT and 12 wk post-RT

Pancreas AdenocarcinomaPancreas AdenocarcinomaSurgical Adjuvant Therapy: RTOG 97Surgical Adjuvant Therapy: RTOG 97--0404Surgical Adjuvant Therapy: RTOG 97Surgical Adjuvant Therapy: RTOG 97 0404

Results in Patients with Pancreatic Head TumorsResults in Patients with Pancreatic Head Tumors

100

80

100

))

CRT + GEMCRT + GEMDead/totalDead/total

138/187138/187CRT + 5CRT + 5--FUFU 161/201161/201

40

60

Aliv

e (%

)A

live

(%)

20

AA

P=0.09P=0.090

0 1 2 3 4 5Years from randomizationYears from randomization

Regine: JAMA 299:1019-1026, 2008

ea s o a do at oea s o a do at o

Survival After PancreaticoduodenectomySurvival After PancreaticoduodenectomyOb ti Adj t Ch di ti ( 1 092)Ob ti Adj t Ch di ti ( 1 092)Observation vs Adjuvant Chemoradiation (n=1,092)Observation vs Adjuvant Chemoradiation (n=1,092)

1.0Adj t th P 0 001Adj t th P 0 001

0 6

0.8

alal

Adjuvant therapy, P<0.001Adjuvant therapy, P<0.001

CRTCRT ObsObsmOSmOS 21.1 mo21.1 mo 15.5 mo15.5 mo

0.4

0.6

Surv

iva

Surv

iva

ChemoradiationChemoradiation

22--yr OSyr OS 44.7%44.7% 22.3%22.3%55--yr OSyr OS 34.6%34.6% 16.1%16.1%

0 0

0.2Observation onlyObservation only

0.00 1 2 3 4 5

FollowFollow--up (years)up (years)

Hu: 2008 GI Symposium, Mayo-Johns Hopkins series

John’s Hopkins John’s Hopkins –– Mayo Clinic Series Mayo Clinic Series pp yyMatchedMatched--Pair AnalysisPair Analysis

•• N=248 Surgery OnlyN=248 Surgery Only•• N=248 Surgery + Adjuvant CRTN=248 Surgery + Adjuvant CRT•• N=248 Surgery + Adjuvant CRTN=248 Surgery + Adjuvant CRT

•• N=496N=496M t h d d i tit ti TM t h d d i tit ti T•• Matched on age, gender, institution, TMatched on age, gender, institution, T--stage, margin positivity, node positivity, stage, margin positivity, node positivity, histologic gradehistologic gradehistologic grade histologic grade

Hu, 2008 GI Symposium

MatchedMatched--Pair Analysis: Survival After Pair Analysis: Survival After P ti d d tP ti d d tPancreaticoduodenectomyPancreaticoduodenectomy

Observation vs Adjuvant Chemoradiation (n=496)Observation vs Adjuvant Chemoradiation (n=496)1.0

0.8

ll

Adjuvant therapy, P<0.001Adjuvant therapy, P<0.001CRTCRT ObsObs

mOSmOS 21.9 mo21.9 mo 14.3 mo14.3 mo

0.4

0.6

Surv

ival

Surv

ival


22--yr OSyr OS 45.5%45.5% 31.4%31.4%55--yr OSyr OS 25.4%25.4% 12.2%12.2%

0.2

SS ChemoradiationChemoradiation

Observation onlyObservation onlyAdj CRT RR: 0.59 (0.48Adj CRT RR: 0.59 (0.48--0.72)0.72)0.0

0 1 2 3 4 5FollowFollow--up (years)up (years)

Observation onlyObservation only

FollowFollow up (years)up (years)Hu: 2008 GI Symposium

S i l Adj t ThS i l Adj t ThPancreas AdenocarcinomaPancreas Adenocarcinoma

Surgical Adjuvant TherapySurgical Adjuvant Therapy5-yr survival (%)

i O C C5-yr survival (%)

i O C C+ margins Obs CT RT-CTGITSG 0 5 - 14

+ margins Obs CT RT-CTGITSG 0 5 - 14EORTC 19% 10 - 20ESPAC-1 28% 11 29 7-13EORTC 19% 10 - 20ESPAC-1 28% 11 29 7-13CONKO-001 19% 9 21 -RTOG 9704 35% - - 22

%

CONKO-001 19% 9 21 -RTOG 9704 35% - - 22

%Mayo – JH 35% 16 35NPCT 0% 8 4 -Mayo – JH 35% 16 35NPCT 0% 8 4 -

Pancreas CancerPancreas CancerRTOG 0848RTOG 0848

Gem x 5 Gem x 5 restagerestageGem x 5 Gem x 5 restagerestage RRRRRT + capegg

if NED:if NED:gg

if NED:if NED: RRRRRRRR Gem

Gem x 5 Gem x 5 restagerestageErlotinib if NEDErlotinib if NEDGem x 5 Gem x 5 restagerestageErlotinib if NEDErlotinib if NED RRRR

RT + cape

GemErlotinib

Pancreatic CancerPancreatic CancerFuture DirectionsFuture Directions

•• Effective systemic therapy?Effective systemic therapy?•• Effective systemic therapy?Effective systemic therapy?•• Advances likely to be in small stepsAdvances likely to be in small steps•• Multiple targets may be requiredMultiple targets may be required•• Maintenance therapy will be requiredMaintenance therapy will be required

•• The importance of local control will The importance of local control will ↑↑I di id li ti f t t tI di id li ti f t t t•• Individualization of treatmentIndividualization of treatment

•• Move towards preoperative therapyMove towards preoperative therapyMove towards preoperative therapyMove towards preoperative therapy

Pancreatic Cancer Relapse PatternsPancreatic Cancer Relapse PatternsppJohns Hopkins Autopsy seriesJohns Hopkins Autopsy series

•• 76 pancreatic cancer autopsies76 pancreatic cancer autopsies•• 76 pancreatic cancer autopsies76 pancreatic cancer autopsies•• 22 resected pts: 73% local relapse22 resected pts: 73% local relapse•• 5/6 positive margin patients local relapse5/6 positive margin patients local relapse•• 88% metastatic disease: some <10 mets, some88% metastatic disease: some <10 mets, some88% metastatic disease: some 10 mets, some 88% metastatic disease: some 10 mets, some

> 1000 mets> 1000 mets•• 30% locally destructive, 70% widely metastatic30% locally destructive, 70% widely metastatic30% locally destructive, 70% widely metastatic 30% locally destructive, 70% widely metastatic •• Loss of DPC4 predictive of widely metastatic Loss of DPC4 predictive of widely metastatic

patternpatternpatternpatternIacobuzio, JCO 27:1806-1813, 2009Iacobuzio, JCO 27:1806-1813, 2009

Pancreatic Cancer Pancreatic Cancer –– Individualized RxIndividualized RxRTOG 1201RTOG 1201

•• Assessment of SMAD4/DPC4 statusAssessment of SMAD4/DPC4 status•• Assessment of SMAD4/DPC4 statusAssessment of SMAD4/DPC4 status

Gem x 3 IMRT 63 Gy + capeIntactIntact

Gem x 3 50.4 Gy + capeLossLoss

FOLFIRINOX x 3 50.4 Gy + cape

Pancreatic Cancer: Pancreatic Cancer: Radiation Radiation T h iT h iTechniqueTechnique

Pancreas CancerPancreas CancerQuality AssuranceQuality Assurance

•• RTOG 9704: decreased survival whenRTOG 9704: decreased survival when•• RTOG 9704: decreased survival when RTOG 9704: decreased survival when RTQA score not per protocolRTQA score not per protocol

Median SMedian S 33--yr OSyr OSCONKOCONKO 001001 2222 34%34%CONKOCONKO--001001 22 mo22 mo 34%34%RTOG 9704RTOG 9704 25 mo25 mo 46%46% ((CA 19CA 19--99 ≤ 90≤ 90

RTQA per protocol)RTQA per protocol)RTQA per protocol)RTQA per protocol)

Regine, International Journal Radiat Oncol Biol Phys 69(3):S78, 2007

Pancreas CancerPancreas CancerDose FractionationDose Fractionation

•• 5040 cGy in 28 fractions is standard for5040 cGy in 28 fractions is standard for•• 5040 cGy in 28 fractions is standard for 5040 cGy in 28 fractions is standard for both unresectable and adjuvantboth unresectable and adjuvant

•• Duodenum is dose limiting for head Duodenum is dose limiting for head tumorstumors

Pancreas CancerPancreas CancerTreatment VolumesTreatment Volumes

•• RTOG 0848 atlasRTOG 0848 atlas•• RTOG 0848 atlasRTOG 0848 atlas•• CTV includes:CTV includes:

•• Proximal CAProximal CA•• Proximal SMAProximal SMAProximal SMAProximal SMA•• PV anterior to SVCPV anterior to SVC•• Preop GTVPreop GTV•• Preop GTVPreop GTV•• PJPJ

A tA t•• AortaAorta

Radiotherapy Radiotherapy –– Traditional fieldsTraditional fields

•• 45 Gy in 25 fractions45 Gy in 25 fractions•• Tumor bedTumor bed•• Lymphatics Lymphatics

(Celiac, SMA, (Celiac, SMA, first echelonfirst echelonfirst echelon first echelon nodes) nodes)

•• Porta hepatisPorta hepatisPorta hepatis Porta hepatis •• Boost tumor bed to Boost tumor bed to

50 4 Gy50 4 Gy50.4 Gy50.4 Gy

Pancreatic CancerPancreatic CancerModern techniqueModern technique

•• IV contrast for GTV delineationIV contrast for GTV delineation•• IV contrast for GTV delineationIV contrast for GTV delineation•• Motion managementMotion management•• Daily IGRTDaily IGRT•• Limited volumesLimited volumes

•• GTV + 10 mm = CTVGTV + 10 mm = CTV•• CTV + 20 mm sup/inf, 10 mm radial = CTV + 20 mm sup/inf, 10 mm radial =

PTVPTV

Pancreas Cancer Planning Pancreas Cancer Planning OAR LimitsOAR Limits

•• Spinal cord max 45 GySpinal cord max 45 Gy•• Spinal cord max 45 GySpinal cord max 45 Gy•• Kidneys combined V18 < 30%Kidneys combined V18 < 30%•• If one kidney V18 < 15%If one kidney V18 < 15%•• Liver mean < 25 Gy, V30 < 50%Liver mean < 25 Gy, V30 < 50%•• Stomach max 54 Gy, V45 <15%Stomach max 54 Gy, V45 <15%Stomach max 54 Gy, V45 <15%Stomach max 54 Gy, V45 <15%•• Small intestine max 54 Gy, V45 < 150 cc, Small intestine max 54 Gy, V45 < 150 cc,

V30 < 300 ccV30 < 300 ccV30 < 300 ccV30 < 300 cc

PancreasPancreasF Fi ld I dF Fi ld I dFour Field IsodosesFour Field Isodoses

Six Field Isodoses

PancreasPancreasDVH C iDVH C i

100

DVH ComparisonDVH Comparison4 Field4 Field 6 Field6 Field

80

100

))

60

ume

(%)

ume

(%)

Right kidneyRight kidney

Left kidneyLeft kidney

20

40

Volu

Volu

Left kidneyLeft kidney Right

kidneyRight kidney

e t d eye t d ey0

000

000

000

000

000

000

0

000

0

000

000

000

000

000

yy kidneykidney

1,00

2,00

3,00

4,00

5,00

6,00

1,00

2,00

3,00

4,00

5,00

6,00

Dose (cGy)Dose (cGy) Dose (cGy)Dose (cGy)

IMRT dose distribution

HEPATOBILIARY MALIGNANCIESHEPATOBILIARY MALIGNANCIES

EpidemiologyEpidemiologyp gyp gy2011 USA2011 USA

•• Liver + IHBDLiver + IHBD•• Liver + IHBDLiver + IHBD•• 26,190 new cases26,190 new cases•• 19,590 deaths19,590 deaths

•• Gall bladder + EHBDGall bladder + EHBDGall bladder EHBDGall bladder EHBD•• 9250 new cases9250 new cases•• 3300 deaths3300 deaths•• 3300 deaths3300 deaths

AMPULLARY CARCINOMAAMPULLARY CARCINOMAAMPULLARY CARCINOMAAMPULLARY CARCINOMA

Ampullary CarcinomaAmpullary Carcinomap yp yRisk FactorsRisk Factors

•• T3T3 T4T4•• T3T3--T4T4•• Positive marginsPositive margins•• Positive nodesPositive nodes•• High histologic gradeHigh histologic grade

Ampullary CancerAmpullary CancerEORTC Ph III T i lEORTC Ph III T i l

80

100EORTC Phase III TrialEORTC Phase III Trial

93 periampullary 93 periampullary

60

80

RT+5FURT+5FU

58% N058% N040 Gy Split40 Gy Split55--FUFU

20

40

ObservObservP=0 737P=0 737

RT+5FURT+5FU

0

20

0 1 2 3 4 5 6 7 8 9 10

ObservObservP=0.737P=0.737

YearsYearsOO NN No. of patients at riskNo. of patients at risk2626 4848 3838 2626 2020 1212 77 44 11 11 112222 4444 3535 2525 1818 1010 88 66 33 33 11

Klinkenbijl: Ann Surg 230:776-784, 1999

2222 4444 3535 2525 1818 1010 88 66 33 33 11

Survival in Node + PatientsSurvival in Node + Patients1.0

P<0.01

Mayo Mayo ––Node + AmpullaryNode + Ampullary

0 6

0.8

rviv

al

0.4

0.6

eral

l su

Adjuvant therapy

0.2Ove

j py

No adjuvant therapy

0.00 2 4 6 8 10

YearsCP1205895B-2

Adapted from Bhatia, IJROBP 66:514-19, 2006

Ampullary CancerAmpullary Cancerp yp yMayoMayo--Johns Hopkins ResultsJohns Hopkins Results

N+N+ N+N+treatmenttreatment Node +Node + Med SMed S SS

surgery (120)surgery (120) 3636 16 mo.16 mo. 6%6%surgery (120)surgery (120) 3636 16 mo.16 mo. 6%6%

S +RT/CT (66)S +RT/CT (66) 4848 32 mo.32 mo. 28%28%

P = 0.004P = 0.004

Narang, Radiation Oncology 6:126, 2011

Survival After Surgical Resection, Node PositiveSurvival After Surgical Resection, Node PositiveObservation vs Adjuvant ChemoradiationObservation vs Adjuvant Chemoradiation Mayo/JHMayo/JHObservation vs Adjuvant Chemoradiation Observation vs Adjuvant Chemoradiation ––Mayo/JHMayo/JH

1.0Adjuvant TherapyAdjuvant Therapy

0 6

0.8

alal

j pyj py

0.4

0.6

Surv

iva

Surv

iva


0.2 P=0.004P=0.004

Observation onlyObservation only0.0

0 2 4 6 8 10YearsYears

yy

YearsYearsNarang: Radiation Oncology 6:126, 2011

CHOLANGIOCARCINOMACHOLANGIOCARCINOMACHOLANGIOCARCINOMACHOLANGIOCARCINOMA

New Cancers in United StatesNew Cancers in United States1 Cholangiocarcinoma1 Cholangiocarcinoma

prostatebreast

80 prostate 80 prostate cancerscancers

115 b t115 b t breastCCA

115 breast 115 breast cancerscancers

Extrahepatic CholangiocarcinomaExtrahepatic Cholangiocarcinomap gp gRadiotherapy IndicationsRadiotherapy Indications

•• Adjuvant therapy following resectionAdjuvant therapy following resection•• Adjuvant therapy following resectionAdjuvant therapy following resection•• Preoperative therapy prior to transplantPreoperative therapy prior to transplant•• Primary therapy Primary therapy

•• EBRT (with chemo)EBRT (with chemo)•• EBRT (with chemo)EBRT (with chemo)•• BrachytherapyBrachytherapy

SBRTSBRT•• SBRTSBRT

Hilar CholangiocarcinomaHilar CholangiocarcinomaggSurgical ResectionSurgical Resection

•• 1515 40% are resectable40% are resectable•• 1515--40% are resectable40% are resectable•• LR after R0 resection: 25LR after R0 resection: 25--40%40%•• Positive margins commonPositive margins common•• Gross residual in 1/3Gross residual in 1/3•• 50% positive nodes50% positive nodes50% positive nodes50% positive nodes•• 55--yr survival 10yr survival 10--40%40%

Hilar CholangiocarcinomaHilar CholangiocarcinomaggSurgical ResectionSurgical Resection

•• LR after R0 resection: 25LR after R0 resection: 25 40%40%•• LR after R0 resection: 25LR after R0 resection: 25--40%40%•• Locoregional first relapse siteLocoregional first relapse site

•• 60% of EHCC60% of EHCC•• 15% Gall Bladder Ca15% Gall Bladder Ca15% Gall Bladder Ca15% Gall Bladder Ca

•• Does RT reduce the risk of locoregional Does RT reduce the risk of locoregional relapse?relapse?relapse?relapse?

Proximal Bile Duct Cancer Proximal Bile Duct Cancer –– Tsukuba UniversityTsukuba UniversityR1 R tiR1 R ti ±± IOERT EBRTIOERT EBRTR1 Resection R1 Resection ±± IOERT, EBRTIOERT, EBRT

Todoroki et al: IJROBPTodoroki et al: IJROBPTodoroki et al: IJROBPTodoroki et al: IJROBP

Proximal Bile Duct Cancer Proximal Bile Duct Cancer –– EORTCEORTCOverall Survival R1 Resection Overall Survival R1 Resection ±± XRTXRT1.0

0.8

%)

%)

P=0.0005P=0.0005

0.4

0.6

rviv

al (%

rviv

al (%

Postoperative radiation (n=38)Postoperative radiation (n=38)

0.2

0.4

SuSu

Surgery alone (n=17)Surgery alone (n=17)

0.00 2 4 6 8 10

M thM th

Surgery alone (n 17)Surgery alone (n 17)

MonthsMonthsGonzales et al: Semin Liver Dis 10:131-41, 1990

Hilar CholangiocarcinomaHilar CholangiocarcinomaggSWOG 0809SWOG 0809

•• Eligibility: T2Eligibility: T2 4 or N1 or margin +4 or N1 or margin +•• Eligibility: T2Eligibility: T2--4 or N1 or margin +4 or N1 or margin +•• Chemo: GemChemo: Gem--Cape x 4 cyclesCape x 4 cycles•• Radiation + capecitabineRadiation + capecitabine

•• 3D: 54003D: 5400 5940 cGy in 305940 cGy in 30 33 fx33 fx•• 3D: 5400 3D: 5400 –– 5940 cGy in 305940 cGy in 30--33 fx33 fx•• IMRT: 5250IMRT: 5250--5500 in 25 fx5500 in 25 fx

•• Goal: 80 patientsGoal: 80 patients•• Endpoints: local relapse and survivalEndpoints: local relapse and survival•• Endpoints: local relapse and survivalEndpoints: local relapse and survival

Hilar CholangiocarcinomaHilar CholangiocarcinomaggAdjuvant RT ConclusionsAdjuvant RT Conclusions

•• Most resected patients at high risk ofMost resected patients at high risk of•• Most resected patients at high risk of Most resected patients at high risk of locoregional relapselocoregional relapse

•• Adjuvant RT may decrease riskAdjuvant RT may decrease risk•• Indications:Indications:Indications:Indications:

•• R1 or R2 resectionR1 or R2 resection•• Positive nodes ?Positive nodes ?•• Positive nodes ?Positive nodes ?•• R0 with close margins (T2R0 with close margins (T2--4)?4)?

•• Caution: liver dose constraintsCaution: liver dose constraints

100

9090

80PTV

70

6060

50

40

30 Liver30

20L kidney

R kidneyLiver

10

0 1000 2000 3000 4000 5000

L kidney

U t bl HilU t bl HilUnresectable Hilar Unresectable Hilar CholangiocarcinomaCholangiocarcinomaCholangiocarcinomaCholangiocarcinoma

Unresectable CholangiocarcinomaUnresectable Cholangiocarcinomagg

•• Radiation + chemoRadiation + chemo liver transplantliver transplant•• Radiation + chemo Radiation + chemo liver transplantliver transplant•• Radiation + CT as primary therapyRadiation + CT as primary therapy

•• DoseDose•• TechniqueTechniqueTechniqueTechnique•• BrachytherapyBrachytherapy

•• LDRLDR•• LDRLDR•• HDRHDR

C li tiC li ti•• ComplicationsComplications

Liver TransplantLiver TransplantppMayo ProtocolMayo Protocol

•• RT: 4500 cGy in 30 bid fractionsRT: 4500 cGy in 30 bid fractions•• RT: 4500 cGy in 30 bid fractionsRT: 4500 cGy in 30 bid fractions•• 3 days bolus 53 days bolus 5--FU during RTFU during RT•• Brachytherapy: 20Brachytherapy: 20--30 Gy with 19230 Gy with 192--IrIr•• Continuous infusion 5Continuous infusion 5--FU or capecitabine FU or capecitabine

until transplantuntil transplant•• Exploratory laparotomyExploratory laparotomy

Liver TransplantLiver TransplantppHilar CholangiocarcinomaHilar Cholangiocarcinoma

•• Rationale:Rationale:•• 2020--30% resectable30% resectable•• > 60% local recurrence rate > 60% local recurrence rate •• Distant mets relatively uncommonDistant mets relatively uncommonDistant mets relatively uncommonDistant mets relatively uncommon

•• Early results disappointing:Early results disappointing:•• 2020--30% survival30% survival•• 50 50 -- 60% tumor recurrence60% tumor recurrence•• 50% of relapses in liver allograft50% of relapses in liver allograft

Liver TransplantLiver TransplantppHilar CholangiocarcinomaHilar Cholangiocarcinoma

SeriesSeries YearYear # Pts# Pts 5 Year Survival5 Year SurvivalSeriesSeries YearYear # Pts# Pts 5 Year Survival5 Year Survival

PittsburghPittsburgh 19951995 2020 20% (320% (3--yr)yr)HannoverHannover 19961996 2525 17%17%BerlinBerlin 19991999 1515 38%38%SpainSpain 20042004 3636 30%30%SpainSpain 20042004 3636 30%30%NordicNordic 20042004 1818 35%35%CanadaCanada 20052005 1010 30% (330% (3--yr)* yr)* Ci i tiCi i ti 20002000 207207 23%**23%**CincinnatiCincinnati 20002000 207207 23%**23%**

**incidental, 8/10 relapseincidental, 8/10 relapse, p, p****+ nodes 7 mo. median survival vs. 35 mo.+ nodes 7 mo. median survival vs. 35 mo.

Patient Survival After TransplantationPatient Survival After Transplantation1993 – 20091993 – 2009

100

708090

10079 + 6%

73 + 5%

506070

All (120)% 63 + 9%

73 + 5%

203040 All (120)

PSC (77)

De Novo (43)

010

0 1 2 3 4 5

De Novo (43)

0 1 2 3 4 5Years after transplantation

September 1, 2009

Patient Survival After Start of TherapyPatient Survival After Start of Therapy1993 – 20091993 – 2009

n=184100

708090

61 + 5%

40506070

% 54 + 4%

203040 All (184)

PSC (111) 42 + 7%

010

0 1 2 3 4 5

De Novo (73)

0 1 2 3 4 5Years after start of therapy

September 1, 2009

Survival after OperationSurvival after Operation

80

100 92%

82% 82%

60

80

82%

40

60%

Transplantation (n=38)48%

20

Transplantation (n=38)Resection (n=26)

21%

00 1 2 3 4 5

Time (years)Ann Surg 2005; 242:451

Explanted Liver AfterN dj t ThNeoadjuvant Therapy

B h thB h thBrachytherapyBrachytherapy

Hilar CholangiocarcinomaHilar CholangiocarcinomaHilar CholangiocarcinomaHilar Cholangiocarcinoma

BrachytherapyBrachytherapyy pyy pyCholangiocarcinomaCholangiocarcinoma

•• Radioactive sources (IridiumRadioactive sources (Iridium 192) placed192) placed•• Radioactive sources (IridiumRadioactive sources (Iridium--192) placed 192) placed in bile ductin bile duct

•• Transhepatic catheters (easy)Transhepatic catheters (easy)•• ERCP placement (hard)ERCP placement (hard)ERCP placement (hard)ERCP placement (hard)•• Low dose rate: 20Low dose rate: 20--30 Gy over 2430 Gy over 24--48 hrs48 hrs•• High dose rate: 4 fractions 4 Gy over 2 High dose rate: 4 fractions 4 Gy over 2

daysdaysyy

BrachytherapyBrachytherapyy pyy py

•• Applicator (≈10F tube) placed Applicator (≈10F tube) placed pp ( ) ppp ( ) pvia endoscope at ERCP via endoscope at ERCP

CTV

duodenum

Liver MetsLiver MetsSBRTSBRT

•• Liver mets: no Rx: med S 3Liver mets: no Rx: med S 3 20 mos20 mos•• Liver mets: no Rx: med S 3Liver mets: no Rx: med S 3--20 mos20 mos•• Resection: 5Resection: 5--yr S 30%+yr S 30%+•• Only 20Only 20--25% suitable for resection25% suitable for resection•• RFA local relapseRFA local relapse

•• < 3 cm 16%< 3 cm 16%•• 33--5 cm 26%5 cm 26%•• > 5 cm 60%> 5 cm 60% 5 cm 60% 5 cm 60%

Liver MetsLiver MetsSBRTSBRT

•• MultiMulti institutional Phase Iinstitutional Phase I II trialII trial•• MultiMulti--institutional Phase Iinstitutional Phase I--II trialII trial•• Ph II dose: 60 Gy in 3 fractionsPh II dose: 60 Gy in 3 fractions•• 22--yr LC 92%yr LC 92%•• 22--yr LC 100% for < 3cmyr LC 100% for < 3cm•• 83% distant progression83% distant progression83% distant progression83% distant progression•• 22--yr OS 30%yr OS 30%

Rusthoven, JCO 27:1572-1578, 2009

Liver Mets Liver Mets --SBRTSBRT

80

100

olol

≤≤3 cm3 cm

60>3 cm>3 cm

l con

tro

l con

tro

20

40

Loca

lLo

cal

00 6 12 18 24 30 36 42 48

MonthsMonths3030 3030 2020 1010 33 111919 1919 1212 88 66 33 33 33>3 cm>3 cm

≤≤3 cm3 cm

Rusthoven: JCO 27:1572-1578, 2009

Liver MetsLiver MetsSBRT TechniqueSBRT Technique

•• Immobilization: custom moldImmobilization: custom mold•• Immobilization: custom moldImmobilization: custom mold•• Active breathing control or abdominal Active breathing control or abdominal

compressioncompression•• Dynamic conformal arcs or multiple nonDynamic conformal arcs or multiple non--Dynamic conformal arcs or multiple nonDynamic conformal arcs or multiple non

coplanar static beams (coplanar static beams (≥ 7)≥ 7)D i ti 80D i ti 80 90% i d90% i d•• Dose prescription: 80Dose prescription: 80--90% isodose90% isodose

•• IGRT: orthogonal xIGRT: orthogonal x--ray or CBCTray or CBCTgg yy

Liver MetsLiver Mets3 fraction SBRT: OAR limits3 fraction SBRT: OAR limits

•• 700 cc nml liver < 15 Gy700 cc nml liver < 15 Gy•• 700 cc nml liver < 15 Gy700 cc nml liver < 15 Gy•• Kidney sum: V15 < 35%Kidney sum: V15 < 35%•• Spinal cord max: 18 GySpinal cord max: 18 Gy•• Chest wall: V30 < 10 ccChest wall: V30 < 10 cc•• Stomach: max 22 Gy, V 16.5 < 10 ccStomach: max 22 Gy, V 16.5 < 10 ccStomach: max 22 Gy, V 16.5 < 10 ccStomach: max 22 Gy, V 16.5 < 10 cc•• Small bowel: max 22 Gy, V 16.5 < 5 ccSmall bowel: max 22 Gy, V 16.5 < 5 cc•• Skin: V30 < 10ccSkin: V30 < 10cc

Liver MetsLiver MetsSBRT CautionsSBRT Cautions

•• RILDRILD•• Bevacizumab: bowel perforationsBevacizumab: bowel perforations

S ft ti iS ft ti i•• Soft tissue necrosisSoft tissue necrosis•• Chest wallChest wall

•• Rib fractureRib fracture•• NeuropathyNeuropathy

•• Biliary fibrosisBiliary fibrosis•• Late vascular toxicityLate vascular toxicity•• Late vascular toxicityLate vascular toxicity

PostPost--test Questiontest QuestionPostPost test Questiontest Question

•• When treating liver metastases with 60When treating liver metastases with 60•• When treating liver metastases with 60 When treating liver metastases with 60 Gy in 3 fraction SBRT, what is the best Gy in 3 fraction SBRT, what is the best dose limit parameter for the liver?dose limit parameter for the liver?dose limit parameter for the liver?dose limit parameter for the liver?a. V30Gy < 50%a. V30Gy < 50%b V15G < 50%b V15G < 50%b. V15Gy < 50%b. V15Gy < 50%c. 700 cc nml liver < 15 Gyc. 700 cc nml liver < 15 Gyd. 700 cc nml liver < 30 Gyd. 700 cc nml liver < 30 Gye. Mean liver dose < 25 Gye. Mean liver dose < 25 Gy

upper gastrointestinal tract malignancies · 2012-04-30 · learning objectiveslearning objectives...

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