Cancer of the Stomach - Sociedade Brasileira de … stomach or GE junction Completely resected (R0)...

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


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


Nodes Resected by D1

5

6

3

4d

4s


N1 N2

N3 N4

128 9

10

11

7

11


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


(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);


Categories of Evidence


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


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


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



Treatment

Category of

Evidence

Observe (2A)

Observe (2A)

Postoperative Treatment

Observe

or

Chemoradiation

or



(2A)

(1)

(1)

Radiation plus concurrent 5FU based

chemotherapy plus 5FU +/- leucovorin

or



(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)


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


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%


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


Nodes Resected by D1

5

6

3

4d

4s


N1 N2

N3 N4

128 9

10

11

7

11


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





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%



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


Perioperative chemotherapy “MAGIC”

(Increasing use of preoperative RT and chemotherapy)

Most Common Regimens in North America



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

Cancer of the Stomach - Sociedade Brasileira de … stomach or GE junction Completely resected (R0)...

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