1. Dept Surgery, Colorectal unit University Hospital, Uppsala, Sweden
Rectal Cancer M62 Coloproctolgy course, Huddersfield
Lars Påhlman
Dept Surgery, Colorectal unit
University Hospital, Uppsala, Sweden

2. Rectal Cancer - focus on surgery
Why focus on surgery ?
The only curative option
Big variation among surgeons
Training mandatory
Surgical strategy important

3. Rectal cancer surgery Two main options Local excision
Abdominal resection

4. Transanal Endoscopic Microsurgery
TEM surgery - adenomas
Transanal Endoscopic Microsurgery
Full thickness excision
Up to 20 cm
Perfect view

5. Rectal cancer surgery Local excision T 1 tumours ‘Early’ T 2 tumours
‘Any T’ fragile patients
TEM - technique crucial

6. Rectal cancer surgery Local tumour control Mesorectum Lateral spread
Intramural spread
Implantation metastases
Nodal involvement

7. Rectal Cancer - focus on surgery
Standard surgery
TME
the gold standard

13. Lateral resection margins Local recurrences / number of patients
Rectal cancer surgery
Lateral resection margins
Local recurrences / number of patients
Pos. lat. marg Neg. lat. marg.
11/13 (85%) /38 (3%)
p < 0.001
Quirke et al. Lancet, nov 1; 1986

14. Hardly ever extend more than
Rectal cancer surgery
Intramural spread
Hardly ever extend more than
0.5 cm
Grinell R. Surg Gynecol Obstet 99: ; 1954

15. Swedish Rectal Cancer Register
5 years follow-up ( )
Local recurrence rate
Irrigation Ant. Resection Hartmann
Yes 96 / % 8 / %
No / % 11 / %
Unknown 7 / % 1 / %
p < n.s.

16. Rectal cancer surgery
Nodal involvement
Proximal
Lateral
Distal

17. Proximal lymph node clearance
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

18. Lateral lymph node clearance
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

19. Rectal cancer surgery Lateral lymph node clearance
Super radical surgery
Positive nodes indicates disseminated disease
Hojo et al; Dis Colon Rectum 32:307, 1989

20. Lateral lymph node clearance
Rectal cancer surgery
Lateral lymph node clearance
Morbidity
Impotence > 60 %
Voiding problem > 40 %
Prolongs surgery

21. Lateral lymph node clearance TME + lateral LN clearance
Rectal cancer surgery
Lateral lymph node clearance
The pivotal trial !
TME + lateral LN clearance vs
Neo - adj. irrad. + TME

22. Distal lymph node clearance Total mesorectal excision
Rectal cancer surgery
Distal lymph node clearance
Total mesorectal excision
How important ?
Heald et al; Br J Surg 1982

23. Distal lymph node clearance Total Mesorectal Excision
Rectal cancer surgery
Distal lymph node clearance
Total Mesorectal Excision
In all cases ?
What is the upper limit ?
Morbidity increased !

24. Abdominoperineal Excision
Rectal cancer surgery
Low rectal cancers
Abdominoperineal Excision
Very difficult surgery !
Important to have correct strategy
Avoid ‘coning’ !
Start early from below !

27. Rectal cancer surgery Conclusion Well - trained surgeons !
TME gold standard !
Lateral lymph nodes - radiotherapy
APR very tricky !
Cone - effect must be avoided

29. 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

30. Resectable Rectal Cancer

31. Meta-analysis rectal cancer radiotherapy
22 trials, patients
Reduction in
overall colorectal isolated
mortality cancer deaths local recurr.
Preoperative:
BED <20 Gy ns ns ns
Gy ns ns 24 ± 15
Gy 10±5* 22 ± 5**** 57 ± 7****
Postoperative:
BED Gy ns 9 ± 7 (ns) 33 ± 11**

32. 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

33. Rectal Cancer Surgery Neoadjuvant radiotherapy will always reduce the
local recurrence rate with  50 %
Irrespective of type of surgery

34. Rectal Cancer Surgery Type of surgery Local recurrence RT - RT +
‘sloppy’ % %
TME % %

35. Adjuvant radiotherapy
Radiation schedule
Conventional fractionation: Gy in weeks
Accelerated fractionation: Gy in 1 week

36. 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

37. Dutch trial - Local recurrence Patients with R 0 (n=1789)
TME alone
5.8% vs 11.4%
p < 0.001
RT + TME

38. Overall Survival eligible patients (n=1809)
TME alone
64.2% vs 63.4%
p = 0.87
RT + TME

39. Cancer specific survival eligible patients (n=1809)
76.1% vs 73.0%
p = 0.18

40. Dutch trial - Local recurrence rate Level from the anal verge
cm cm cm
10.5% vs 11.9%
p = 0.53

41. SWEDISH RECTAL CANCER TRIAL
Local recurrence rate (min. 5 years)
(patients operated on for cure)
Preop. irrad Surgery alone p-value
Ant. res % (18 / 206) 21 % (41 / 194) < 0.001
Abd. per % (22 / 243) 25 % (65 / 256) < 0.001
Other op % ( 2 / 6 ) 38 % ( 3 / 8 )

42. Local recurrence rate Trial / level Local recurrence RT - RT + p value
SRCT < 5 cm 27 % % TME < 5 cm 11 % 12 %
SRCT cm 26 % 9 % < TME cm 15 % 4 % < 0.001
SRCT > 10 cm 12 % 8 % TME > 10 cm % 4 %

43. Swedish Rectal Cancer Register
Data report
 15,000 patients ( 1,500 yearly)
Base - line data
Trends in treatment
5-year oncological data

44. Local recurrence % ( )
All patients R 0 surgery

45. Local recurrence % ( )
cm cm

46. 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 radio- therapy on an individual level)

47. 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)

48. Non - Resectable Rectal Cancer

49. Rectal cancer Non-resectable Must be identified preop.
Malpractice if not treated with preoperative irradiation

50. Non-resectable rectal cancer
No uniform definition
(T4’s growing into a another often non-resectable organ/tissue)
%, half without distant metastases
Causes much suffering
Surgery alone likely cures very few
Preop. prolonged radio(chemo)therapy is mandatory

51. 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 !)

52. Non-resectable rectal cancer
Uppsala trial
Prospective randomised trial
46 Gy vs
40 Gy + MFL

53. Non-resectable rectal cancer
Uppsala trial ; 3 years follow-up
Irrad. + chemo Irrad. alone
Local recurrence patients 27 patients
All resected patients (10 %) (26 %)
Curative resection (12 %) (30 %)
Local control (89 %) 20 (74 %)

54. Non-resectable rectal cancer
Uppsala trial ; 3 years follow-up
Irrad. + chemo Irrad. alone
Survival patients 36 patients
Alive (35 %) (22 %)
Median follow-up months 53 months
Dead (65 %) 28 (78 %)
Median survival months 21 months

55. Non-resectable rectal cancer
Uppsala trial
Conclusion
The trial was under-powered
Chemo-radiotherapy more toxic
A trend favouring irrad. + MFL

56. Non-resectable rectal cancer
Is RT/CT superior to RT in non-resectable rectal cancer ?
Probably, but the evidence is low
One ! trial is ongoing (Nordic)

57. Non-resectable rectal cancer
LARCS
Nordic prospective randomised trial
50 Gy (during 5 weeks) vs
50 Gy FU / Lv

58. Non-resectable rectal cancer
Preop. prolonged chemo - radiotherapy
% resectable
% long-term cure

59. Sphincter Preservation

60. Adjuvant radiotherapy
Rectal cancer
Sphincter preservation
A myth or reality ?

61. Rectal cancer - down sizing
Rullier E et al

62. 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:

63. 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:

64. 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:

65. CAO/ARO/AIO - trial in Germany
Trial design
Preop. chemorad.
Postop. chemorad. R a n d o m i s t L o c a l R e u r S u r v i a l

66. CAO/ARO/AIO - trial in Germany
Down staging
Preop. chemorad. Postop. chemorad.
No tumour %
Stage I % %
Stage II % %
Stage III % %
Stage IV % %

67. CAO/ARO/AIO - trial in Germany
Local recurrence rate
N Engl J Med 2004; 351:

68. CAO/ARO/AIO - trial in Germany
Overall Survival
N Engl J Med 2004; 351:

69. CAO/ARO/AIO - trial in Germany
Sphincter preservation
Preop. Postop.
chemorad. chemorad.
Preserved spincters 26/ % 13/ %
Total material % %

70. EORTC 22921 (1011 patients) Trial design
Preop. Radiotherapy
45 Gy
Preop. chemorad.
45 Gy Fu/Lv R a n d o m i s t L o c a l R e u r S u r v i a l

71. EORTC 22921 (1011 patients) Down staging
Preop. irrad. Preop. chemorad.
Path. compl. resp % %
p <

72. Sphincter preservation
EORTC (1011 patients)
Sphincter preservation
Preop. irrad. Preop. chemorad.
Ant. resection % %
p = 0.05

73. FFCD 9203 (762 patients) Trial design
Preop. Radiotherapy
45 Gy
Preop. chemorad.
45 Gy Fu/Lv R a n d o m i s t L o c a l R e u r S u r v i a l

74. FFCD 9203 (762 patients) Down staging
Preop. irrad. Preop. chemorad.
Path. compl. resp % %
p = 0.05

75. Sphincter preservation
FFCD (762 patients)
Sphincter preservation
Preop. irrad. Preop. chemorad.
Ant. resection % %
p > 0.05

76. Sphincter preservation - Polish trial
Trial design
Preop. chemorad x 2 Gy
Preop. radiotherapy x 5 Gy R a n d o m i s t L o c a l R e u r S u r v i a l S p h i n c t e r s v

77. 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

78. Sphincter preservation - Polish trial
Sphincter preservation according to allocated radiotherapy
Planned 5x5 Gy RT/CT
APR % %
APR/AR % %
AR % %

79. Sphincter preservation - Polish trial
Sphincter preservation according to allocated radiotherapy
5x5 Gy N = RT/CT N = 156
61 % %

80. Adjuvant radiotherapy
Rectal cancer
Sphincter preservation
Still a myth ?

81. Neo - adjuvant radiotherapy
To whom ?
Better preop. staging !

82. Neo - adjuvant radiotherapy
Preop. local staging
Rectal examination
Ultrasound
MRI

83. Neo - adjuvant radiotherapy
Rectal cancer
No preop. radiotherapy
Stage I tumours i.e. uT 1 or uT 2
Rectal Ultrasound very good

84. 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

85. 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

86. Neo - adjuvant radiotherapy
To whom ?
Large bulky tumour
Narrow male pelvis
Tumours growing anteriorly
Abdominoperineal excision

87. 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

88. Neo - adjuvant radiotherapy
Radiation biology
P 53 an important marker
A tumour with mutated P responds less good to radiotherapy and 5-Fu based chemotherapy
Kressner et al, J Clin Oncol 1999

89. 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 % !

90. Rectal Cancer 2005 Conclusion Appropriate staging !
Consider radiotherapy !
Well trained surgeon !!
Chemotherapy ?

92. Colorectal Tripartite Meeting
Royal Dublin Society
5th-7th July 2005
Further details from
Closing date for abstracts 10th December 2004