Rectal Cancer
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Transcript Rectal Cancer
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