Gastrointestinal Cancer

R. Zenhusern

Rectal Cancer

Anatomic Location of CRC

Cecum

14 %

Ascending colon

10 %

Transverse colon

12 %

Descending colon

7 %

Sigmoid colon

25 %

Rectosigmoid junct.9 %

Rectum

23 %

70%

Epidemiology

Increasing Incidence of CRC

Incidence 30-40 / 100000 / year

>70 y. of age 300 / 100000 / year

third most common malignant disease

second most common cause of cancer

death

Epidemiology

1998: 4000 new cases in Switzerland

More than 350 women an 600 men die
each year due to CRC

70% of CRC are resectable at diagnosis

Mortality has decreased

Decreasing mortality of CRC

5-year Survival
1960-70

1980-90

Colon cancer

40-45%

60%

Rectal cancer

35-40%

58%

WHO Classification of CRC

Adenocarcinoma in situ / severe dysplasia

Adenocarcinoma
Mucinous (colloid) adenocarcinoma (>50% mucinous)
Signet ring cell carcinoma (>50% signet ring cells)
Squamous cell (epidermoid) carcinoma
Adenosquamous carcinoma
Small-cell (oat cell) carcinoma
Medullary carcinoma
Undifferentiated Carcinoma

Clinical Staging of CRC

TNM
stage

Primary
tumor

Lymph-node
metastasis

Distant
metastasis

Dukes
stage

Astler-Coller
modified
Dukes stage

Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

A1

T2

N0

M0

B1

T3

N0

M0

B2

T4

N0

M0

B2

any T

N1

M0

C1/C2

any T

N2, N3

M0

C1/C2

Stage IV

any T

any N

M1

Stage II
Stage III

TNM Classification
Tis

T1

T2 T3

T4

Mucosa
Muscularis mucosae
Submucosa

Muscularis propria

Subserosa

Serosa
Extension
to an adjacent
organ

Stage and Prognosis

Stage

5-year Survival (%)

0,1

Tis,T1;No;Mo

> 90

I
II

T2;No;Mo
T3-4;No;Mo

80-85
70-75

III

T2;N1-3;Mo

70-75

III
III

T3;N1-3;Mo
T4;N1-2;Mo

50-65
25-45

IV

M1

<3

Adjuvant Chemotherapy
of Colon Cancer
Therapy

relapse-free
5-year Survival

Overall
Survival

Surgery

62 %

78 %

Surgery
+ 6x 5-FU/Lv

71 %

83 %

Adjuvant chemotherapy of colon cancer

The IMPACT analysis for stages B and C disease1
5FU=370-400 mg/m2 D1 to D5 + FA 200 mg/m2 D1 to D5
(every 28 days 6 cycles)
n=736
Control

n=757

Probability of survival

Overall
survival

35% reduction of recurrence

1.0
Stage B
0.8
0.6
Stage C
0.4
0.2

Overall
survival
Probability of survival

22% reduction in death

1.0
Stage B

0.8
0.6

Stage C
0.4
0.2
0

1
2
3
Time from randomization (years)

1
2
3
Time from randomization (years)

Patients at risk
Control, Stage B
Fluorouracil/folinic acid Stage B

423
418

403
399

327
328

189
188

Patients at risk
Control, Stage B
Fluorouracil/folinic acid Stage B

423
418

347
357

256
262

139
140

56
60

Control, Stage C
Fluorouracil/folinic acid Stage C

334
318

298
300

225
231

125
161

Control, Stage C
Fluorouracil/folinic acid Stage C

334
318

223
250

141
179

69
118

28
42

1IMPACT

investigators. Lancet.1995;345:939-944.

Purpose of Radio(chemo)therapy
in Rectal Cancer

To lower local failure rates and improve survival in

resectable cancers

to allow surgery in primarly inextirpable cancers

to facilitate a sphincter-preserving procedure

to cure patients without surgery: very small

cancer or very high surgical risk

Rectal Cancer

Surgery is the mainstay of treatment of RC

After surgical resection, local failure is common
Local recurrence after conventional surgery:
15%-45% (average of 28%)
Radiotherapy significantly reduces the number
of local recurrences

Radiotherapy in the management of RC

In at least 28 randomised trials the value of either

preoperative or postoperative RT has been tested

Preoperative RT (30+Gy): 57% relative reduction

of local failure
Postoperative RT (35+Gy): 33% relative reduction

Colorectal Cancer Collaborative Group. Lancet 2001;358:1291

Gamma C. JAMA 2000;284:1008

Adjuvant Therapy of Rectal Cancer

1990 US NIH Consensus Conference

Postoperative chemoradiotherapy =
standard of care for RC Stage II,II

The consensus statement was based upon the

results of three randomised trials

Postoperative radiochemotherapy
Number of pts.

GITSG NCCTG
202
204

NSABP-R01
555

Surgery alone LF (%)

24

25

S (%)
Radiotherapy LF (%)
S (%)
Chemotherapy LF (%)
S (%)
Chemoradioth. LF (%)
S (%)

43
20
52
27
21
11
59

43
16
41
21
53
8
58

25
47

14

ESMO Recommendations

Resectable cases

Surgical procedure: TME

Preoperative RT: recommended
Postoperative chemoradiotherapy: T3,4 or N+

Non-resectable cases: local recurrences

Preoperative RT with or without CT

Optimal combination of chemo- radiotherapy?

If radiochemotherapy is used
postoperatively, protacted infusion of
5-FU is superior to bolus 5-FU during
radiotherapy
O`Connell. NEJM 1994;331:331

Protacted Infusion of 5-FU

660 patients with stage II,III rectal cancer

Local recurrence
4-year DFS
4-year OS

PI-FU

Bo-FU

ns
63%
70%

ns
53%
60%

p=0.11
p=0.01
p=0.005

O`Connell. NEJM 1994;331:331

Preoperative RT in resectable RC
Swedish Rectal Cancer Trial
1168 patients randomised to 25 Gy (5x5) PRT or no RT
Surgery alone

Preop. RT

Rate of local recurrence

27%

11%

p<0.001

5-year overall survival

48%

58%

p=0.004

Swedish Rectal Cancer Trial. NEJM 1997;336:980

Predicting risk of recurrence in RC

Surgery-related

Tumor-related

-Low anterior resection

-Anatomic location

-Excision of the mesorectum

-Histologic type

-Extend of lymphadenectomy

-Tumor grade

-postoperative anastomotic

-Pathologic stage

leakage
-Tumor perforation

-radial resection margin

-neural, venous, lymphatic
invasion

Incidence of local failure in RC

T1-2,No,Mo
T3,No,Mo
T1,N1,Mo
T3-4,N1-2,Mo

<10%
15-35%
15-35%
45-65%

Total Mesorectal Excision (TME)

Local recurrence rates after surgical

resection of RC have decreased from about
30% to < 10%

1. Radio(chemo)therapy
2. Importance of circumferential margin (TME)

Total Mesorectal Excision (TME)

TME series with local recurrence rates of 5%

Other series report recurrence rates of 5-15%
Inclusion of patients with T1-2,No disease
Experience of the surgeon is important
Higher complication rates

TME will not remove all tumor cells in the pelvis

in all patients, RT may eradicate th remaining
ones

TME +/- preoperative RT

Dutch Colorectal Cancer Group

1861 patients randomised TME vs PRT+TME

Recurrence rate
OS

TME
2.4%
ns

PRT+TME
8.2%
ns

Kapiteijn E. NEJM 2001;345:638

Preoperative therapy for

sphincter preservation

Phase II data with no randomised trials

Optimal regimen not known
Long-term functional outcome?
Five of seven trials report sphincter
preservation in approximately 75%

Preoperative Therapy in locally

advanced/non-resectable rectal cancer

Favourable treatment results in phase II trials

with preoperative radiochemotherapy
Chemoradiotherapy was viewed as standard based
on phase II data

Preoperative vs. Postoperative

chemoradiotherapy for rectal cancer

Randomized trial of the German Rectal Cancer

study Group: Sauer R et al. N Engl J Med 2004;351:1731-40

cT3 or cT4 or node-positive rectal cancer

50,4 Gy (1.8 Gy per day)

5-FU: 1000 mg/m2 per day (d1-5)

during 1. and 5. week

Preoperative vs. Postoperative

chemoradiotherapy for rectal cancer
Preop CRT Postop CRT

Patients
5 y. OS
5 y. local relapse
G3,4 toxic effects

Increase in sphincter-preserving surger<y with preop Th.

N=415
76%
6%
27%

N=384
74%
p=0.8
13%
p=0.006
40%
p=0.001

Sauer R et al. N Engl J Med 2004;351:1731-40

Capecitabine in combination with

preoperative radiotherapy

Phase I/II studies demonstrate that capecitabine

is effective and well tolerated in combination with
preoperative radiotherapy
Capecitabine 825 mg/m2 twice daily given
continously with standard RT can be recommended
Phase II trials are ongoing

PETACC-6: capecitabine + RT vs. Capecitabine

+Oxalipaltin +RT

R. Glynne-Jones. Annals of Oncology 2006;17:361-371

Capecitabine in combination with

preoperative radiotherapy

Phase II study in locally advanced rectal cancer

53 pat. with T3, N0-2, T4, N0-2 cancer
Capecitabine 825 mg/m2 twice daily for 7 days/week
and concomitant RT (50.4 Gy/28 fractions)
Overall response:
58%
Downstaging rate:
57%
Pathological CR:
24%
Sphincter-saving Op: 59% (20/34 pat. <5cm )

A.De Paoli et al. Annals of Oncology 2006;17:246-251

Chemotherapy with preoperative

radiotherapy in rectal cancer

Adding fluorouracil-based chemotherapy to

preoperative or postoperative RT has no
significant influence on survival.
Chemotherapy before or after surgery, confers a
significant benefit with respect to local control.

Bosset JF et al. N Engl J Med 2006;355:1114-1123

Esophageal Cancer

Esophageal Cancer

Lifetime risk: 0.8% for men, 0.3% for women

Mean age at diagnosis 67 years
Sixth leading cause of death from cancer
Overall incidence: 5 /100000 persons
Relative incidence of squamous-cell to
adenocarcinoma decreased
from 2:1 (1988) to 1.2:1 (1994)

Surgery for Esophageal cancer

Five-year survival after complete surgical removal

of the tumor:

Stage 0:
Stage I:
Stage IIA:
Stage IIB:
Stage III:

95%
50-80%
30-40%
10-30%
10-15%

Preoperative RT for Esophageal cancer

Five randomized trials (>100 pat.) have

compared preoperative RT with immediate
surgery
Total dose of RT: 20 40 Gy
None of the studies demonstrated a
survival advantage

Arnott SJ et al. Int J Radiat Oncol Biol Phys 1998;41:579-583

Preoperative CT for Esophageal cancer

A randomized US study (N=440) showed no

benefit: 3 cycles cisplatin / fluorouracil
2y survival 35% vs 37%

Kelsen et al. N Engl J Med 1998;339:1979-1984

A randomized British study (N=802)

suggested an increase in survival
2 y survival 43% vs 34%

MRC Oesophageal Cancer Working Group. Lancet

2002;359:1727-1733

Preoperative CT and RT
for Esophageal cancer

Eight randomized trials ( seven negativ, one showed a benefit)

Study

Le Prise 1994
Apinop 1994
Walsh 1996
Bosset 1997
Urba 2001
Burmeister 2002

CT

41/45 C/F
34/35 C/F
55/58 C/F
139/143 C
50/50 CVF
128/128 C/F

RT
20 Gy
40 Gy
40 Gy
37 Gy
40 Gy
35 Gy

MS

3yS

(mo)

(%)

10/10
7/10
11/16
19/19
18/17
22/19

9/17
20/26
6/32
37/39
16/30

Nonsurgical CT and RT

Cisplatin / Fluorouracil and RT (50 Gy)

Long-term survival in approximately 25 %
Increasing the radiation dose was
unsuccessful

Minsky BD et al. J Clin Oncol 2002;20:1167-1174

Gastric Cancer

Gastric Cancer

9.9% of all new cancer diagnosis

12% of all cancer deaths
Overall 5 y. survival 15%-35%
Declining incidence in the West

Surgery for Gastric Cancer

Stage I:
5y survival 58%-78%
Stage II:
5y survival 34%
Local or regional recurrence after gastric
resection with curative intent: 40-65%
Adjuvant chemoradiotherapy ?

CRT after surgery vs.

surgery alone

Randomized trial n=556, T1-4, No-2

Resected adenocarcinoma of the stomach or
gastroesophageal junction

1 cycle leucovorin 20mg/m2, Fluorouracil 425 mg/m2 day 1-5

RT 45 Gy (1.8Gy per day), beginning on day 28
Lv 20mg/m2, FU 400 mg/m2 d. 1-4 and last 3 d. of RT
2 cycles leucovorin 20mg/m2, Fluorouracil 425 mg/m2 day 1-5
MacDonald et al. N Engl J Med 2001;345:725-730

CRT after surgery vs.

surgery alone

Results:

3y survival
Med. OS
3y RFS
Local reccurence

CRT

Surgery

50%
36 mo
48%
19%

41%
27 mo
31%
29%

p=0.005

MacDonald et al. N Engl J Med 2001;345:725-730

Perioperative chemotherapy vs.

surgery alone

Randomized trial: n=503

Chemotherapy:

3 preoperative and 3 postoperative cycles

Epirubicin 50mg/m2, cisplatin 60mg/m2, day1
Fluorouracil cont i.v. 200mg/m2, day 1-21

Cunningham et al. N Engl J Med 2006;355:11-20

Perioperative chemotherapy vs.

surgery alone

Results:

CT

5y OS
36.3%
Local recurrence 14.45%

Surgery

23%
20.6%

Cunningham et al. N Engl J Med 2006;355:11-20