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Rectal Cancer - 2005
M62 Coloproctolgy course, Huddersfield
Lars Påhlman
Dept Surgery, Colorectal unit
University Hospital, Uppsala,
Sweden
Rectal Cancer - focus on surgery
Why focus on surgery ?




The only curative option
Big variation among surgeons
Training mandatory
Surgical strategy important
Rectal cancer surgery
Two main options
 Local excision
 Abdominal resection
TEM surgery - adenomas
Transanal
Endoscopic
Microsurgery
 Full thickness
excision
 Up to 20 cm
 Perfect view
Rectal cancer surgery
Local excision




T 1 tumours
‘Early’ T 2 tumours
‘Any T’ fragile patients
TEM - technique crucial
Rectal cancer surgery
Local tumour control





Mesorectum
Lateral spread
Intramural spread
Implantation metastases
Nodal involvement
Rectal Cancer - focus on surgery
Standard surgery
TME
the gold standard
Rectal cancer surgery
Lateral resection margins
Local recurrences / number of patients
Pos. lat. marg.
11/13 (85%)
Neg. lat. marg.
1/38 (3%)
p < 0.001
Quirke et al. Lancet, nov 1; 1986
Rectal cancer surgery
Intramural spread
Hardly ever extend more than
0.5 cm
Grinell R. Surg Gynecol Obstet 99: 421-430; 1954
Swedish Rectal Cancer Register
5 years follow-up (1995 - 97)
Local recurrence rate
Irrigation
Ant. Resection
Yes
No
Unknown
96 / 1464 7 %
44 / 398 11 %
7 / 65
11 %
p < 0.001
Hartmann
8 / 71 11 %
11 / 115 10 %
1 / 17
6%
n.s.
Rectal cancer surgery
Nodal involvement
 Proximal
 Lateral
 Distal
Rectal cancer surgery
Proximal lymph node clearance
High-tie
 No effect on survival
 + nodes = disseminated disease
Grinell; Surg Gynecol Obstet 120:1031, 1965
Pezim and Nicholls; Ann Surg 200:729, 1984
Rectal cancer surgery
Lateral lymph node clearance
Super radical surgery
 Extended pelvic lymphadenectomy
 Retro-peritoneal clearance
 Extra mesenteric clearance
Hojo et al; Dis Colon Rectum 32:307, 1989
Rectal cancer surgery
Lateral lymph node clearance
Super radical surgery
Positive nodes indicates disseminated
disease
Hojo et al; Dis Colon Rectum 32:307, 1989
Rectal cancer surgery
Lateral lymph node clearance
Morbidity
 Impotence > 60 %
 Voiding problem > 40 %
 Prolongs surgery
Rectal cancer surgery
Lateral lymph node clearance
The pivotal trial !
TME + lateral LN clearance
vs
Neo - adj. irrad. + TME
Rectal cancer surgery
Distal lymph
node clearance
Total mesorectal
excision
How important ?
Heald et al; Br J Surg 1982
Rectal cancer surgery
Distal lymph node clearance
Total Mesorectal Excision
 In all cases ?
 What is the upper limit ?
 Morbidity increased !
Rectal cancer surgery
Low rectal cancers
Abdominoperineal Excision




Very difficult surgery !
Important to have correct strategy
Avoid ‘coning’ !
Start early from below !
Rectal cancer surgery
Conclusion





Well - trained surgeons !
TME gold standard !
Lateral lymph nodes - radiotherapy
APR very tricky !
Cone - effect must be avoided
Role of radiotherapy in rectal cancer
 To lower local failure rates and
improve survival in resectable
cancers
 To allow surgery in non-resectable
cancers
 To facilitate a sphincter-preserving
procedure in low-lying cancers ?
 To cure patients without (major)
surgery
Resectable
Rectal Cancer
Meta-analysis rectal cancer radiotherapy
22 trials, 8 507 patients
Preoperative:
BED
<20 Gy
20 - 30 Gy
30 - 37.5 Gy
Postoperative:
BED 35 - 44 Gy
Reduction in
overall
colorectal
mortality cancer deaths
isolated
local recurr.
ns
ns
10±5*
ns
ns
22 ± 5****
ns
24 ± 15
57 ± 7****
9 ± 7 (ns)
33 ± 11**
ns
Radiotherapy in resectable cancer
Conclusions from the meta-analysis
 Radiotherapy works (with standard surgery)
lowers local failure rates
improves survival
 Dose-response relationship (for preop RT)
low doses ineffective
 Preop RT is more dose-efficient than postop
seen in the Uppsala-trial comparing pre- and
postop RT
Rectal Cancer Surgery
Neoadjuvant radiotherapy
will always reduce the
local recurrence rate with  50 %
Irrespective of type of surgery
Rectal Cancer Surgery
Type of surgery
‘sloppy’
TME
Local recurrence
RT RT +
30 %
13 %
10 %
6%
Adjuvant radiotherapy
Radiation schedule
 Conventional fractionation:
45 - 50 Gy in 4 - 5 weeks
 Accelerated fractionation:
25 Gy in 1 week
Adjuvant radiotherapy
Ongoing trial in Sweden
3-armed trial
 25 Gy / 1 week
immediate surgery
 25 Gy / 1 week
delayed surgery
 50 Gy / 5 weeks
delayed surgery
Dutch trial - Local recurrence
Patients with R 0 (n=1789)
,20
TME alone
Local recurrence (%)
,15
5.8% vs 11.4%
p < 0.001
,10
,05
RT + TME
0,00
0
2
4
Years since surgery
6
8
Overall Survival
eligible patients (n=1809)
1,0
TME alone
,9
,8
,7
64.2% vs
63.4%
p = 0.87
,6
,5
RT + TME
,4
Cum Survival
,3
,2
,1
0,0
0
2
4
Years since surgery
6
8
Cancer specific survival
eligible patients (n=1809)
1,0
,8
76.1% vs 73.0%
p = 0.18
,6
,4
,2
,0
0
2
4
Years since surgery
6
8
Dutch trial - Local recurrence rate
Level from the anal verge
0 - 5 cm
cm
6 - 10 cm
11 - 15
,20
,15
,15
,15
,10
Local recurrence (%)
,20
Local recurrence (%)
,20
,10
,05
10.5% vs 11.9%
p = 0.53
,10
,05
0,00
,05
0,00
0
2
4
Years since surgery
6
8
0,00
0
2
4
Years since surgery
6
8
0
2
4
Years since surgery
6
8
SWEDISH RECTAL CANCER TRIAL
Local recurrence rate
(min. 5 years)
(patients operated on for cure)
Preop. irrad .
Ant. res.
9 % (18 / 206)
Abd. per. 9 % (22 / 243)
Other op. 33 % ( 2 / 6 )
Surgery alone
21 % (41 / 194)
25 % (65 / 256)
38 % ( 3 / 8 )
p-value
< 0.001
< 0.001
Local recurrence rate
Trial / level
SRCT < 5 cm
TME
< 5 cm
SRCT 6 - 10 cm
TME 6 - 10 cm
SRCT > 10 cm
TME > 10 cm
Local recurrence
RT RT +
p value
27 % 10 %
11 % 12 %
26 % 9 %
15 % 4 %
12 % 8 %
6% 4%
0.003
0.53
< 0.001
< 0.001
0.3
0.15
Swedish Rectal Cancer Register
Data report
1995 - 2004
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 15,000 patients ( 1,500 yearly)
Base - line data
Trends in treatment
5-year oncological data
Local recurrence % (1995 - 98)
All patients
R 0 surgery
12
12
10
10
8
8
6
6
4
Ej preoperativ strålbehandling (1981 pat)
Preoperativ strålbehandling (1597 pat)
2
4
Ej preoperativ strålbehandling (1495 pat)
Preoperativ strålbehandling (1353 pat)
2
0
0
1
2
3
Överlevnadstid (år)
4
5
0
0
1
2
3
Överlevnadstid (år)
4
5
Local recurrence % (1995 - 1997)
0 - 6 cm
16
14
34 rec
7 - 15 cm
16
1 rec
11 rec
14
7 rec
12
12
10
10
34 rec
8
4 rec
72 rec
8
4 rec
1 rec
6
6
7 rec
4
4
2
2
0
0
Främre resektion
Abd.amp.
Preoperativ strålbehandling
Hartmann
Ej preoperativ strålbehandling
33 rec
Främre resektion
Abd.amp.
Preoperativ strålbehandling
Hartmann
Ej preoperativ strålbehandling
Rectal cancer treatment what have we learned ?
 Local failures can more or less be eliminated;
< 3 % (not only  10 %)
 Survival slightly improved about 10 % with
some morbidity (TME + RT)
 The challenge is to preoperatively find those
who need more than surgery and predict
where the tumour cells are (to use radiotherapy on an individual level)
Preoperative chemo-radiotherapy
in rectal cancer
Is RT/CT superior to RT in resectable
rectal cancer ?
Probably, but the evidence is low
Two !
trials are ongoing (EORTC)
(France)
Non - Resectable
Rectal Cancer
Rectal cancer
Non-resectable
Must be identified preop.
Malpractice if not treated
with preoperative irradiation
Non-resectable rectal cancer
 No uniform definition
(T4’s growing into a another often non-resectable
organ/tissue)
 10 - 15%, half without distant metastases
 Causes much suffering
 Surgery alone likely cures very few
 Preop. prolonged radio(chemo)therapy is
mandatory
Non-resectable rectal cancer
Evidence for chemo-radiotherapy ?
 one positive? randomised trial (Moertel 1969)
 two negative randomised trials with increased
toxicity (RTOG 1985, Danish 1993)
 one positive? randomised trial (Swedish, 2001)
 lots of phase II data (data are impressed !)
Non-resectable rectal cancer
Uppsala trial 1988 - 96
Prospective randomised trial
46 Gy
vs
40 Gy + MFL
Non-resectable rectal cancer
Uppsala trial 1988 - 96; 3 years follow-up
Irrad. + chemo
Irrad. alone
29 patients
27 patients
All resected patients
3 (10 %)
7 (26 %)
Curative resection
3 (12 %)
7 (30 %)
26 (89 %)
20 (74 %)
Local recurrence
Local control
Non-resectable rectal cancer
Uppsala trial 1988 - 96; 3 years follow-up
Irrad. + chemo
Irrad. alone
Survival
34 patients
36 patients
Alive
12 (35 %)
8 (22 %)
62 months
53 months
22 (65 %)
28 (78 %)
27 months
21 months
Median follow-up
Dead
Median survival
Non-resectable rectal cancer
Uppsala trial 1988 - 96
Conclusion
 The trial was under-powered
 Chemo-radiotherapy more toxic
 A trend favouring irrad. + MFL
Non-resectable rectal cancer
Is RT/CT superior to RT in nonresectable rectal cancer ?
Probably, but the evidence is low
One !
trial is ongoing (Nordic)
Non-resectable rectal cancer
LARCS
Nordic prospective randomised trial
50 Gy (during 5 weeks)
vs
50 Gy + 5-FU / Lv
Non-resectable rectal cancer
Preop. prolonged chemo - radiotherapy
40 - 70 % resectable
20 - 30 % long-term cure
Sphincter
Preservation
Adjuvant radiotherapy
Rectal cancer
Sphincter preservation
A myth or reality ?
Rectal cancer - down sizing
Rullier E et al
The Lyon R90-01 Trial
Study design
 T2- /T3- tumours
 39 Gy (13 x 3 Gy)
 Randomised to immediate surgery or
surgery 5 weeks after irradiation
J Clin Oncol 1999; 17: 2396-2402
The Lyon R90-01 Trial
Study design
Surgeons where asked before any
treatment to evaluate the possibility
for performing a sphincter saving
procedure
J Clin Oncol 1999; 17: 2396-2402
The Lyon R90-01 Trial
Local recurrence
Overall 9 %
12 % in the group of patients
where the surgeon had planned a
APR but it was changed after
irradiation
J Clin Oncol 1999; 17: 2396-2402
CAO/ARO/AIO - trial in Germany
Trial design
R
a
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d
o
m
i
s
a
t
i
o
n
Preop. chemorad.
Postop. chemorad.
L
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R
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r
S
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CAO/ARO/AIO - trial in Germany
Down staging
Preop. chemorad.
No tumour
8%
Postop. chemorad.
-
Stage I
26 %
18 %
Stage II
30 %
30 %
Stage III
29 %
43 %
Stage IV
6%
8%
CAO/ARO/AIO - trial in Germany
Local recurrence rate
N Engl J Med 2004; 351: 1731-40
CAO/ARO/AIO - trial in Germany
Overall Survival
N Engl J Med 2004; 351: 1731-40
CAO/ARO/AIO - trial in Germany
Sphincter preservation
Preop.
Preserved spincters
Total material
Postop.
chemorad.
chemorad.
26/75 35 %
13/74 18 %
69 %
71 %
EORTC 22921
(1011 patients)
Trial design
R
a
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d
o
m
i
s
a
t
i
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n
Preop. Radiotherapy
45 Gy
Preop. chemorad.
45 Gy + 5-Fu/Lv
L
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R
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S
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EORTC 22921
(1011 patients)
Down staging
Path. compl. resp
Preop. irrad.
Preop. chemorad.
14 %
5.3 %
p < 0.001
EORTC 22921
(1011 patients)
Sphincter preservation
Preop. irrad.
Ant. resection
55.6 %
Preop. chemorad.
52.4 %
p = 0.05
FFCD 9203
(762 patients)
Trial design
R
a
n
d
o
m
i
s
a
t
i
o
n
Preop. Radiotherapy
45 Gy
Preop. chemorad.
45 Gy + 5-Fu/Lv
L
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R
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S
u
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v
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FFCD 9203
(762 patients)
Down staging
Path. compl. resp
Preop. irrad.
Preop. chemorad.
11 %
3%
p = 0.05
FFCD 9203
(762 patients)
Sphincter preservation
Ant. resection
Preop. irrad.
Preop. chemorad.
52 %
52 %
p > 0.05
Sphincter preservation - Polish trial
Trial design
R
a
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d
o
m
i
s
a
t
i
o
n
Preop. chemorad.
25 x 2 Gy
Preop. radiotherapy
5 x 5 Gy
L
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Sphincter preservation - Polish trial
Entry criteria
 Tumour reached by digital exam but no
sphincters infiltration
 T3 and resectable T4
 1 cm macroscopic distal margin is
sufficient
Sphincter preservation - Polish trial
Sphincter preservation according to
allocated radiotherapy
Planned
5x5 Gy
RT/CT
APR
26 %
21 %
APR/AR
68 %
61 %
AR
85 %
88 %
Sphincter preservation - Polish trial
Sphincter preservation according to
allocated radiotherapy
5x5 Gy
N = 155
61 %
RT/CT
N = 156
58 %
Adjuvant radiotherapy
Rectal cancer
Sphincter preservation
Still a myth ?
Neo - adjuvant radiotherapy
To whom ?
Better preop. staging !
Neo - adjuvant radiotherapy
Preop. local staging
Rectal examination
Ultrasound
MRI
Neo - adjuvant radiotherapy
Rectal cancer
No preop. radiotherapy
Stage I tumours i.e. uT 1 or uT 2
Rectal Ultrasound very good
Neo - adjuvant radiotherapy
Rectal cancer
Preop. Short - term radiotherapy
Stage II and III tumours i.e. > uT 2
All APR´s
Rectal Ultrasound not so useful
MRI for the circumferential margin
Neo - adjuvant radiotherapy
Rectal cancer
Neo adjuvant chemo - radiotherapy
Large tumours i.e. advanced T 3 and T 4
Rectal Ultrasound not good
MRI best
Neo - adjuvant radiotherapy
To whom ?
 Large bulky tumour
 Narrow male pelvis
 Tumours growing anteriorly
 Abdominoperineal excision
Neo - adjuvant radiotherapy
Why APR´s ?
 Very tricky surgery
 A low cancer has the highest risk
for lateral lymph node involvement
 No anastomosis with less risk of late
adverse effects
Neo - adjuvant radiotherapy
Radiation biology
 P 53 an important marker
 A tumour with mutated P 53
responds less good to radiotherapy
and 5-Fu based chemotherapy
Kressner et al, J Clin Oncol 1999
Neo - adjuvant radiotherapy
Conclusion
 Tailored treatment based upon MRI
and ultrasound
 Consider P 53 measurement
 Local recurrence rates (over all)
should not be more than 10 % !
 Local recurrence rates after R0
resections less than 3 % !
Rectal Cancer
Conclusion
 Appropriate staging !
 Consider radiotherapy !
 Well trained surgeon !!
 Chemotherapy ?
2005
Colorectal Tripartite Meeting
Royal Dublin Society
5th-7th July 2005
Further details from www.tripartite.org.uk
Closing date for abstracts 10th December
2004