UPPER UPPER UPPER UPPER GASTROINTESTINAL GASTROINTESTINAL TRACT MALIGNANCIES TRACT MALIGNANCIES Michael G. Haddock M.D. Michael G. Haddock M.D. M Cli i M Cli i Mayo Clinic Mayo Clinic ASTRO Spring Refresher ASTRO Spring Refresher A il 13 2012 A il 13 2012 April 13, 2012 April 13, 2012
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UPPER GASTROINTESTINAL TRACT MALIGNANCIES · 2012-04-30 · Learning ObjectivesLearning Objectives • Describe the indications for the use ofDescribe the indications for the use
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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
•• 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
•• 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
•• 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
•• 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
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%
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
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
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
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
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)
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
**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
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
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%
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
Jemal, Ca Cancer J Clin 61:69-90,2011
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)
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
•• 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
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
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
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
Hundahl, Annals of Surgical Oncology 9:278-286, 2002
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
•• 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
Hundahl, Annals of Surgical Oncology 9:278-286, 2002
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
*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
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
Remaining Remaining Tumor Bed Tumor Bed TN StageTN Stage Stomach Stomach Volumes* Volumes* Nodal VolumesNodal Volumes
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
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
Remaining Remaining Tumor Bed Tumor Bed TN StageTN Stage Stomach Stomach Volumes* Volumes* Nodal VolumesNodal Volumes
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+
•• 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
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,
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
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
•• 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
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
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
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
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
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: 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
Kagoshima University Study (Japan)Locally Advanced Disease:
Kagoshima University Study (Japan)
• 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
Pancreas AdenocarcinomaPancreas AdenocarcinomaL ll Ad d DiL ll Ad d DiLocally Advanced DiseaseLocally Advanced Disease
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
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
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
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
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)
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
•• 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
•• 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
•• 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
•• 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
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
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
•• 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
•• 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
•• 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)?
•• 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
•• 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%
•• 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
•• 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