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Cancer of the Stomach
B.J. Cummings
2009
Cancer of the Stomach
B.J. Cummings
2009
Outline
• Epidemiology and Patterns of Failure
• Lymph node resection
• The major clinical trials• The major clinical trials
• Radiation treatment
• Gastroesophageal junction cancers
Outline
Epidemiology and Patterns of Failure
Gastroesophageal junction cancers
Stomach, Males
Age-Standardized Incidence Rate per 100,000
Stomach, Males
Standardized Incidence Rate per 100,000
Gastric Cancer Epidemiology
• Third most common cancer in the world
• Incidence falling – North America, Europe by 3
Brazil 1.6% per year; Argentina 2.3% per year
• Cancers in fundus and pylorus declining more than in cardia• Cancers in fundus and pylorus declining more than in cardia
• Etiology - Tobacco smoking; food conservation practices; H.Pylori infection; high salt consumption; esophageal
reflux disease
Gastric Cancer Epidemiology
Third most common cancer in the world
North America, Europe by 3-4% per year
Brazil 1.6% per year; Argentina 2.3% per year
Cancers in fundus and pylorus declining more than in cardiaCancers in fundus and pylorus declining more than in cardia
Tobacco smoking; food conservation practices; H.Pylori infection; high salt consumption; esophageal
Incidence Rates and Mortality: Incidence Ratios
(Males)
Cancer Central/South America North America
Stomach
Incidence 22.0 7.4
MIR 0.75 0.57
ColorectalColorectal
Incidence 14.3 44.4
MIR 0.51 0.34
Esophagus
Incidence 5.9 5.8
MIR 0.92 0.88
Kamangar, JCO 2006; 24:2137. (rates per 100,000 person
Incidence Rates and Mortality: Incidence Ratios
(Males)
Cancer Central/South America North America
Incidence 22.0 7.4
MIR 0.75 0.57
Incidence 14.3 44.4
MIR 0.51 0.34
Incidence 5.9 5.8
MIR 0.92 0.88
Kamangar, JCO 2006; 24:2137. (rates per 100,000 person-years)
Two Staging Systems
UICC/AJCC Tumor Node Metastasis
Japan Tumor Node Distant
T – comparable
N – UICC/AJCC by number involved
Japan by location
M – comparable
Stage groupings – some differences
Two Staging Systems
etastasis
ode Distant Metastasis Peritoneum Hepatic
by number involved
by location
some differences
Survival After Surgery5yr Survival (percent)
Stage USA
1982-1987
11,087 cases
I 50
II 29
III 13
IV 3
All 19
Note: USA (AJCC) and Japanese staging systems differ
Fuchs, N Engl J Med 1995; 333:32
Survival After Surgery5yr Survival (percent)
Japan
1987
11,087 cases
1971-1985
3,176 cases
91
72
44
9
50
Note: USA (AJCC) and Japanese staging systems differ
Patterns of Recurrence Following Surgery
Pattern USA Series88 failures/130 cases
Any failure
Local-regional 56%
Peritoneal 34%
Distant (not peritoneal) 60%
Landry, Int J Radiat Oncol Biol Phys 1990; 19:1357; Katai, Dig Surg 1994; 11:99
Patterns of Recurrence Following Surgery
USA Series88 failures/130 cases
Any failure
Japan Series687 failures/1976 cases
Clinically dominant failure
56% 23%
34% 44%
60% 24%
Landry, Int J Radiat Oncol Biol Phys 1990; 19:1357; Katai, Dig Surg 1994; 11:99
Potential Sources of RecurrencePositive Resection Margins
Radial and Longitudinal
3 series (each n>100)
854 patients
Positive margin Average (range)
854 patients
Blieberg, Eur J Surg Oncol 15: 535, 1989; Sievert, Dtsch Med Woch 112: 662, 1987;
Allum, Br J Cancer 60: 739, 1989
Potential Sources of RecurrencePositive Resection Margins
Radial and Longitudinal
Positive margin Average (range)
22% (18-23%)22% (18-23%)
Blieberg, Eur J Surg Oncol 15: 535, 1989; Sievert, Dtsch Med Woch 112: 662, 1987;
Potential Sources of RecurrenceExtension to Serosa
Serosa
NegativeNegative
Positive
All had D2/D3 node dissection
Roukos, Br J Cancer 2001; 84:1602
Potential Sources of RecurrenceExtension to Serosa
Relapse Rate(percent)
5 – 145 – 14
61 – 73
Potential Sources of RecurrenceImmunohistochemical Positive Node Metastases
Primary within wall T1-2N0 4 series (n=296)
Primary beyond wall T3-4N0 3 series (n=144)
Incidence of IH +ve in N+ve cases not known
Status of unresected nodes not known
Location of IH +ve nodes unpredictable
Smalley, ASTRO 2004
Potential Sources of RecurrenceImmunohistochemical Positive Node Metastases
IH Positive Average (Range)
4 series (n=296) 26% (16-36%)
3 series (n=144) 56% (43-65%)
Incidence of IH +ve in N+ve cases not known
Location of IH +ve nodes unpredictable
1
5
4s2
Gastric Lymph Node Stations
5
6
3
4d
4s
Hartgrink, J Clin Oncol 22: 2069, 2004
N1 N2
N3 N4
128 9
10
11
7
11
Gastric Lymph Node Stations
16
13
1615
14
14
Measures to Reduce FailureMore Extensive Node Dissection
Japanese Classification
Japanese
Nomenclature 1981
D1 All perigastric nodes and greater and lesser omentumD1 All perigastric nodes and greater and lesser omentum
(“over D1” D1 with retrieval of at least 20
D2 Additional regional nodes around branches of celiac axis
D3 More extended regional nodes
D4 Paraaortic nodes
Measures to Reduce FailureMore Extensive Node Dissection
Japanese Classification
Nodes removed
All perigastric nodes and greater and lesser omentumAll perigastric nodes and greater and lesser omentum
(“over D1” D1 with retrieval of at least 20-25 nodes)
Additional regional nodes around branches of celiac axis
More extended regional nodes
1
5
4s2
Gastric Lymph Node Stations
Nodes Resected by D1
5
6
3
4d
4s
Hartgrink, J Clin Oncol 22: 2069, 2004
N1 N2
N3 N4
128 9
10
11
7
11
Gastric Lymph Node Stations
Nodes Resected by D1-D2 Procedures
16
13
1615
14
14
Limited (D1) vs More Extended (D2) Node Dissection
Study Patients Overall Survival
UKMRC 400 Not different
Netherlands 711 Not differentNetherlands 711 Not different
Italy 162
Cuschieri, Br J Cancer 1999; 79:1522; Bonenkamp, N Engl J Med 1999; 340:908
Degiuli, Eur J Surg Oncol 2004; 30:303
* mortality worse if splenectomy and pancreatectomy in D2 dissection.
Limited (D1) vs More Extended (D2) Node Dissection
Overall Survival Op. Mortality
Not different D2 worse*
Not different D2 worse*Not different D2 worse*
- Not different
Cuschieri, Br J Cancer 1999; 79:1522; Bonenkamp, N Engl J Med 1999; 340:908
* mortality worse if splenectomy and pancreatectomy in D2 dissection.
Current Approaches to Lymphadenectomy
USA/Europe D1, with intent to obtain/examine
at least 15 nodes.
Japan D2 is standard
Current Approaches to Lymphadenectomy
D1, with intent to obtain/examine
at least 15 nodes.
D2 is standard
National Comprehensive Cancer Network
NCCN Clinical Practice Guidelines in Oncology
Gastric Cancer
V.2. 2009V.2. 2009
www.nccn.org
National Comprehensive Cancer Network
NCCN Clinical Practice Guidelines in Oncology
Gastric Cancer
V.2. 2009V.2. 2009
NCCN Practice Guidelines V.2. 2009
Category
(1) High level (for example, randomized trial);
uniform NCCN panel consensus.
Categories of Evidence
uniform NCCN panel consensus.
(2A) Lower level; uniform NCCN consensus.
(2B) Lower level; nonuniform NCCN consensus
(but no major disagreement).
(3) Any level of evidence, but reflects major
disagreement.
High level (for example, randomized trial);
uniform NCCN panel consensus.
Categories of Evidence
uniform NCCN panel consensus.
Lower level; uniform NCCN consensus.
Lower level; nonuniform NCCN consensus
(but no major disagreement).
Any level of evidence, but reflects major
Stage(no distant metastases) Treatment
T1b Surgery
Primary Treatment
NCCN Practice Guidelines V.2. 2009
T1b Surgery
T2 or higher
or N+ve
Surgery
Preop. Chemotherapy (ECF)
Preop. Chemoradiation
ECF=Epirubicin, Cisplatin, 5FU
Treatment
Category of
Evidence
Surgery (2A)
Primary Treatment
Surgery (2A)
Surgery
or
Preop. Chemotherapy (ECF)
or
Preop. Chemoradiation
(2A)
(1)
(2B)
Stage(RO resection) Treatment
Tis or T1N0 Observe
T2N0 Observe
NCCN Practice Guidelines V.2. 2009
Postoperative Treatment
T2N0 Observe
or
Chemoradiation
or
Chemotherapy (ECF) if
received preoperatively
T3, T4 or
Any T, N+ve
Radiation plus concurrent 5FU based
chemotherapy plus 5FU +/
or
Chemotherapy (ECF) if
received preoperatively
Treatment
Category of
Evidence
Observe (2A)
Observe (2A)
Postoperative Treatment
Observe
or
Chemoradiation
or
Chemotherapy (ECF) if
received preoperatively
(2A)
(1)
(1)
Radiation plus concurrent 5FU based
chemotherapy plus 5FU +/- leucovorin
or
Chemotherapy (ECF) if
received preoperatively
(1)
(1)
• CT simulation and 3D planning recommended
• Target volumes (Refer to detailed descriptions of gastric
bed and nodal stations at risk according to location and
extent of primary tumor)
NCCN Practice Guidelines V.2. 2009
Principles of Radiation Therapy
extent of primary tumor)
• Limit dose to normal structures (kidneys, liver,
spinal cord, heart, lungs, residual stomach, jejunum etc)
• Dose 45-50.4Gy (1.8Gy/day)
• Supportive therapy – Nutrition; antacids; antiemetics, etc.
CT simulation and 3D planning recommended
Target volumes (Refer to detailed descriptions of gastric
bed and nodal stations at risk according to location and
Principles of Radiation Therapy
Limit dose to normal structures (kidneys, liver,
spinal cord, heart, lungs, residual stomach, jejunum etc)
50.4Gy (1.8Gy/day)
Nutrition; antacids; antiemetics, etc.
The Most Influential Trials
in North America
• European trials of extended node dissection
• North American trial of postoperative radiation• North American trial of postoperative radiation
and chemotherapy
• (UK trial of perioperative chemotherapy)
The Most Influential Trials
in North America
European trials of extended node dissection
North American trial of postoperative radiationNorth American trial of postoperative radiation
(UK trial of perioperative chemotherapy)
The Two “Major” Trials
Author N
Adjuvant
Treatment
Local Recurrence
S
Macdonald 556Postop
29Macdonald 556Postop
RTCT29
Cunningham 503 Periop CT 21
The Two “Major” Trials
Local Recurrence
(%)
Overall Survival
(%)
S
S +
Adjuvant S
S +
Adjuvant
29 19 41* 50* (3yr)29 19 41* 50* (3yr)
21 14 23* 36* (5yr)
*p statistically significant
Postoperative Chemoradiotherapy
Overall Survival
Macdonald, N Engl J Med 2001; 345:725
Postoperative Chemoradiotherapy
Comment
D2 surgery 10%
(D1 36%; D0 54%)
Compliance 64%
Local recurrence 19% vs 29%Local recurrence 19% vs 29%
5FU/FA x 1; RT 45Gy/5wk,
5FU/FA x 2; 5FU/FA x 2.
Macdonald, N Engl J Med 2001; 345:725
Perioperative Chemotherapy
D2 surgery 41
Compliance: Preop 86%; Postop 50%
Local recurrence 14% vs 21%
Overall Survival
Local recurrence 14% vs 21%
ECF x 3 preop; x3 postop
Cunningham, N Engl J Med 2006; 355:11
Perioperative Chemotherapy
Comment
D2 surgery 41-45%
Compliance: Preop 86%; Postop 50%
All cycles 42%
Local recurrence 14% vs 21%Local recurrence 14% vs 21%
ECF x 3 preop; x3 postop
Cunningham, N Engl J Med 2006; 355:11
Adjuvant Chemotherapy
• More than 30 randomized trials, of varying quality.
• Benefit more common, and pronounced, in some
Asian studies.Asian studies.
• Marginal benefit in Western studies.
• Absolute improvement in 5yr survival about 4%.
Adjuvant Chemotherapy
More than 30 randomized trials, of varying quality.
Benefit more common, and pronounced, in some
Marginal benefit in Western studies.
Absolute improvement in 5yr survival about 4%.
Postoperative Chemotherapy
Overall Survival
Sakuramoto, N Engl J Med 2007; 357:1810
Postoperative Chemotherapy
Comment
D2 surgery standard (94%)
Compliance: 12 months 66%
Local recurrence 6% vs 12%
S-1 (fluoropyrimidine) for 1 year
Sakuramoto, N Engl J Med 2007; 357:1810
Postoperative Adjuvant ChemoradiationPostoperative Adjuvant Chemoradiation
Gastric Adjuvant Int 0116
Randomized after complete resection to:
• Observation
• Radiation plus chemotherapy
Macdonald, N Engl J Med 345: 725, 2001
• Radiation plus chemotherapy
Gastric Adjuvant Int 0116
Randomized after complete resection to:
Radiation plus chemotherapyRadiation plus chemotherapy
Gastric Adjuvant Int 0116Eligibility
Adenoca stomach or GE junction
Completely resected (R0)
Node positive and/or penetration of muscularis propriaNode positive and/or penetration of muscularis propria
(Stratified by Node and T status)
Performance status ≤ ECOG 2, adequate organ function
Caloric intake > 1500 kcal per day
Adjuvant treatment start within 48 days of surgery
Gastric Adjuvant Int 0116Eligibility
Adenoca stomach or GE junction
Node positive and/or penetration of muscularis propriaNode positive and/or penetration of muscularis propria
(Stratified by Node and T status)
ECOG 2, adequate organ function
Caloric intake > 1500 kcal per day
Adjuvant treatment start within 48 days of surgery
Gastric Adjuvant Int 0116Treatment
Chemotherapy
• 5FU 425mg/m2/d and FA 20mg/m
28 days before RTCT, and 2 cycles each 28 days beginning
28 days after completion of RT28 days after completion of RT
• 5FU 400mg/m2/d and FA 20mg/m
and d 1-3 of week 5 of RT
Radiation
• 45Gy/1.8Gy per fraction/5 weeks
Gastric Adjuvant Int 0116Treatment
/d and FA 20mg/m2/d given d 1-5 one cycle
28 days before RTCT, and 2 cycles each 28 days beginning
/d and FA 20mg/m2/d on d 1-4 of week 1,
45Gy/1.8Gy per fraction/5 weeks
Gastric Adjuvant Int 0116Radiation Volume
• Primary tumour bed
• Regional lymphatics, including perigastric, splenic,
pancreatico-duodenal, porta hepatis, celiac, local paraaortic pancreatico-duodenal, porta hepatis, celiac, local paraaortic
(plus lower paraesophageal)
• Distal duodenum/stomach remnant and proximal anastomosis
plus 2cm margin
• Field arrangement generally opposed anterior
Gastric Adjuvant Int 0116Radiation Volume
Regional lymphatics, including perigastric, splenic,
duodenal, porta hepatis, celiac, local paraaortic duodenal, porta hepatis, celiac, local paraaortic
Distal duodenum/stomach remnant and proximal anastomosis
Field arrangement generally opposed anterior-posterior
Gastric Adjuvant Int 0116Overall Survival
Macdonald, New Engl J Med 345:725, 2004
Gastric Adjuvant Int 0116Overall Survival
p=0.005HR1.35
Gastric Adjuvant Int 0116Failure Patterns
Failure Area Surgery
Local(stomach or tumour bed)(stomach or tumour bed)
Regional(liver, intra-abdominal nodes,
peritoneum)
Distant(outside peritoneal cavity)
Gastric Adjuvant Int 0116Failure Patterns (percent)
Surgery Surgery + RTCT
19 719 7
46 27
12 13
Gastric Adjuvant Int 0116Toxicity Gd 3 or Greater
Hematologic 54
Gastrointestinal 33
Flu Like 9
Infection 6Infection 6
Compliance (percent)
Treatment completed 65
Stopped due to toxicity 17
Not completed – other 18
Gastric Adjuvant Int 0116Toxicity Gd 3 or Greater (percent)
Death 1 (3 patients)
Postop Chemoradiotherapy Adds Benefit After
D2 Lymphadenectomy
Locoregional Failure
Macdonald
(local)
Kim
(loco-
Surgery plus 19% 15%
Macdonald, N Engl J Med 2001;345:725 (n=556; D0
Kim, Int J Radiat Oncol Biol Phys 2005;63:1279 (n=990; D2 dissection 87%)
Surgery plus
adjuvant19% 15%
Surgery 29% 22%
p value NR 0.005
Postop Chemoradiotherapy Adds Benefit After
D2 Lymphadenectomy
Locoregional Failure 5yr Survival
Kim
-regional)
Macdonald Kim
15% 45% 57%
Macdonald, N Engl J Med 2001;345:725 (n=556; D0-D1 dissection 90%)
Kim, Int J Radiat Oncol Biol Phys 2005;63:1279 (n=990; D2 dissection 87%)
15% 45% 57%
22% 30% 51%
0.005 0.005 0.019
Radiation TreatmentRadiation TreatmentRadiation TreatmentRadiation Treatment
Stomach Bed
Preoperative
Stomach Bed
Postoperative
1
5
4s2
Gastric Lymph Node Stations
Nodes Resected by D1
5
6
3
4d
4s
Hartgrink, J Clin Oncol 22: 2069, 2004
N1 N2
N3 N4
128 9
10
11
7
11
Gastric Lymph Node Stations
Nodes Resected by D1-D2 Procedures
16
13
1615
14
14
Marked Simulator Film
Willett and Gunderson, Perez and Brady, 5th Edition, 2008
Marked Simulator Film
Edition, 2008
Gastric Adjuvant Int 0116Radiation Quality Assurance
243 Plans reviewed prior to and following RT
Initial review
Final review
Sites of deviation of initial review
Tumour bed
Lymph nodes
Anastomosis/stump
Normal organs
Gastric Adjuvant Int 0116Radiation Quality Assurance
243 Plans reviewed prior to and following RT
35% major or minor deviation
6.5% major deviation
Sites of deviation of initial review
21%
20%
11%
9.5%
Some RT Techniques
• Dose optimized conformal planning, using 5 to 6 coplanar beams
a) Anterior-posterior
b) 5 field split volume
c) Conformal
• Dose optimized conformal planning, using 5 to 6 coplanar beams
• Node volumes include those encompassed by “D2” dissection
• Patient immobilized supine in Body
d) IMRT
Some RT Techniques
Dose optimized conformal planning, using 5 to 6 coplanar beamsDose optimized conformal planning, using 5 to 6 coplanar beams
Node volumes include those encompassed by “D2” dissection
Patient immobilized supine in Body-Fix cast
Stomach Movement
• Considerable interfractional and intrafractional movement
• Whole stomach
For systematic and random errorsFor systematic and random errors
3.5cm S-I; 4.0cm R-L; 6.0cm A
(Watanabe, Radiother Oncol 2008; 87:425)
• Residual stomach following surgery
4-D CT planning; diaphragm movement on fluoroscopy, etc
• Image – guided treatment
Stomach Movement
Considerable interfractional and intrafractional
For systematic and random errorsFor systematic and random errors
L; 6.0cm A-P
(Watanabe, Radiother Oncol 2008; 87:425)
Residual stomach following surgery
D CT planning; diaphragm movement on fluoroscopy, etc
5-Field Split Volume
AP and PA fields
Right lateral
field
AP field
Field Split Volume
Isocentre
Left lateral
field
Isocentre
Split Volume RT Reduces Toxicity
Study Patients RT Technique
INT 0116 281 AP:PAINT 0116 281 AP:PA
PMH 205 field conformal
Half-beam block
Macdonald, N Eng J Med 2001; Ringash, Clin Oncol 2005
Split Volume RT Reduces Toxicity
RT TechniqueToxicity ≥Gd 3
(percent)
Compliance (percent)
Hematol GI
54 33 6554 33 65
5 field conformal
beam block15 20 95
HTV
CTV
PTV
1
5
4
1
2
3
HTV
CTV
PTV
5-F Conformal Plan IMRT Plan
Supportive Care
• Nutrition, review weekly
• Prophylactic antinauseants. eg. Ondansetron, Stemetil
Prophylactic H-2 blocker. eg. Ranitidine (?long term)• Prophylactic H-2 blocker. eg. Ranitidine (?long term)
• CBC weekly during treatment, then monthly
• B12, Fe, Folate, Vitamins etc. as indicated
• (standard meal 1 hour before planning and treatment)
Supportive Care
Prophylactic antinauseants. eg. Ondansetron, Stemetil
2 blocker. eg. Ranitidine (?long term)2 blocker. eg. Ranitidine (?long term)
CBC weekly during treatment, then monthly
B12, Fe, Folate, Vitamins etc. as indicated
(standard meal 1 hour before planning and treatment)
Adenocarcinoma of the
Gastroesophageal Junction
Adenocarcinoma of the
Gastroesophageal Junction
Siewert Types
Is there an Advantage for Chemotherapy?
Cunningham, N Engl J Med 2006. Perioperative ECF
Macdonald N Engl J Med 2001. Postoperative RT, 5FU, Folinic Acid.
No difference by site.
Is there an Advantage for Chemotherapy?
Cunningham, N Engl J Med 2006. Perioperative ECF
Macdonald N Engl J Med 2001. Postoperative RT, 5FU, Folinic Acid.
No difference by site.
Preoperative Radiation (40Gy/4wk) for
Adenoca of the Gastric Cardia
Zhang, Int J Radiat Oncol Biol Phys 1998; 42:929
Preoperative Radiation (40Gy/4wk) for
Adenoca of the Gastric Cardia
Preoperative Radiation (40Gy/4wk) for
Adenoca of the Gastric Cardia
Tolerance
RT plus Surgery
n=171
Op mortality 1%
Zhang, Int J Radiat Oncol Biol Phys 1998; 42:929
Anastomotic leak 2%
Failure Sites
Local 39%
Nodal 39%
Distant 24%
Preoperative Radiation (40Gy/4wk) for
Adenoca of the Gastric Cardia
RT plus Surgery Surgery p value
n=199
2.5% ns
4% ns
52% <0.03
55% <0.01
25% ns
Most Common Regimens in North America
Gastric
Postoperative RT and chemotherapy “Macdonald”
Gastroesophageal junction
Postoperative RT and chemotherapy “Macdonald”
Perioperative chemotherapy “MAGIC”
(Increasing use of preoperative RT and chemotherapy)
Most Common Regimens in North America
Postoperative RT and chemotherapy “Macdonald”
Postoperative RT and chemotherapy “Macdonald”
Perioperative chemotherapy “MAGIC”
(Increasing use of preoperative RT and chemotherapy)
Ongoing Clinical Trials Which Include Radiation Therapy
(Phase III)
Country Timing
USA Adjuvant
Netherlands Perioperative
Korea Adjuvant
NCI Clinical Trials Register, 2009
Ongoing Clinical Trials Which Include Radiation Therapy
(Phase III)
Treatments
5FU-leucovorin, RT-5FU
vs
Epirubicin, Cisplat, 5FU
Epirubicin, Cisplat, Capecitabine,
+/- Postop RT
RT, Cisplat, Capecitabine
vs
Epirubicin, Cisplat, Capecitabine
ASTRO COURSE PRESENTATIONS
PRESENTATIONS CAN BE ACCESSED AT THE
FOLLOWING FTP SITE UNTIL ABOUT MID
SEPTEMBERSEPTEMBER
ftp://Brazil2009:Brazil*[email protected]/
Username: Brazil2009
Password: Brazil*2009
ASTRO COURSE PRESENTATIONS
PRESENTATIONS CAN BE ACCESSED AT THE
FOLLOWING FTP SITE UNTIL ABOUT MID-
ftp://Brazil2009:Brazil*[email protected]/
HTV
CTV
PTV