Gastrointestinal Cancer
R. Zenhäusern
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
A
A
Stage I
T1
N0
M0
A
A1
T2
N0
M0
A
B1
T3
N0
M0
B
B2
T4
N0
M0
B
B2
A
any T
N1
M0
C
C1/C2
B
any T
N2, N3
M0
C
C1/C2
Stage IV
any T
any N
M1
D
D
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
0
1.0
Stage B
0.8
0.6
Stage C
0.4
0.2
0
0
1
2
3
Time from randomization (years)
0
1
2
3
Time from randomization (years)
4
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
N
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