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Rectal Cancer - 2005 M62 Coloproctolgy course, Huddersfield. Lars Påhlman Dept Surgery, Colorectal unit University Hospital, Uppsala, Sweden. Why focus on surgery ? The only curative option Big variation among surgeons Training mandatory

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Rectal Cancer - 2005M62 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 - focus on surgery
rectal cancer surgery
Two main options

Local excision

Abdominal resection

Rectal cancer surgery
tem surgery adenomas
TEM surgery - adenomas

Transanal Endoscopic Microsurgery

  • Full thickness excision
  • Up to 20 cm
  • Perfect view
rectal cancer surgery1
Local excision

T 1 tumours

‘Early’ T 2 tumours

‘Any T’ fragile patients

TEM - technique crucial

Rectal cancer surgery
rectal cancer surgery2
Local tumour control

Mesorectum

Lateral spread

Intramural spread

Implantation metastases

Nodal involvement

Rectal cancer surgery
rectal cancer surgery3
Lateral resection margins

Local recurrences / number of patients

Pos. lat. marg. Neg. lat. marg.

11/13 (85%) 1/38 (3%)

p < 0.001

Quirke et al. Lancet, nov 1; 1986

Rectal cancer surgery
rectal cancer surgery4
Intramural spread

Hardly ever extend more than

0.5 cm

Grinell R. Surg Gynecol Obstet 99: 421-430; 1954

Rectal cancer surgery
swedish rectal cancer register
5 years follow-up (1995 - 97)

Local recurrence rate

Irrigation Ant. Resection Hartmann

Yes 96 / 1464 7 % 8 / 71 11 %

No 44 / 398 11 % 11 / 115 10 %

Unknown 7 / 65 11 % 1 / 17 6 %

p < 0.001n.s.

Swedish Rectal Cancer Register
rectal cancer surgery6
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
rectal cancer surgery7
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
rectal cancer surgery8
Lateral lymph node clearance

Super radical surgery

Positive nodes indicates disseminated disease

Hojo et al; Dis Colon Rectum 32:307, 1989

Rectal cancer surgery
rectal cancer surgery9
Lateral lymph node clearance

Morbidity

Impotence > 60 %

Voiding problem > 40 %

Prolongs surgery

Rectal cancer surgery
rectal cancer surgery10
Lateral lymph node clearance

The pivotal trial !

TME + lateral LN clearance

vs

Neo - adj. irrad. + TME

Rectal cancer surgery
rectal cancer surgery11
Rectal cancer surgery

Distal lymph node clearance

Total mesorectal excision

How important ?

Heald et al; Br J Surg 1982

rectal cancer surgery12
Distal lymph node clearance

Total Mesorectal Excision

In all cases ?

What is the upper limit ?

Morbidity increased !

Rectal cancer surgery
rectal cancer surgery13
Low rectal cancers

Abdominoperineal Excision

Very difficult surgery !

Important to have correct strategy

Avoid ‘coning’ !

Start early from below !

Rectal cancer surgery
rectal cancer surgery14
Conclusion

Well - trained surgeons !

TME gold standard !

Lateral lymph nodes - radiotherapy

APR very tricky !

Cone - effect must be avoided

Rectal cancer surgery
role of radiotherapy in rectal cancer
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
meta analysis rectal cancer radiotherapy
Meta-analysis rectal cancer radiotherapy

22 trials, 8 507 patients

Reduction in

overall colorectal isolated

mortality cancer deaths local recurr.

Preoperative:

BED <20 Gy ns ns ns

20 - 30 Gy ns ns 24 ± 15

30 - 37.5 Gy 10±5* 22 ± 5**** 57 ± 7****

Postoperative:

BED 35 - 44 Gy ns 9 ± 7 (ns) 33 ± 11**

radiotherapy in resectable cancer
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 surgery15
Neoadjuvant radiotherapy

will always reduce the

local recurrence rate with  50 %

Irrespective of type of surgery

Rectal Cancer Surgery
rectal cancer surgery16
Type of surgery Local recurrence

RT - RT +

‘sloppy’ 30 % 10 %

TME 13 % 6 %

Rectal Cancer Surgery
adjuvant radiotherapy
Radiation schedule

Conventional fractionation: 45 - 50 Gy in 4 - 5 weeks

Accelerated fractionation: 25 Gy in 1 week

Adjuvant radiotherapy
adjuvant radiotherapy1
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

Adjuvant radiotherapy
dutch trial local recurrence patients with r 0 n 1789
Dutch trial - Local recurrencePatients with R 0 (n=1789)

TME alone

5.8% vs 11.4%

p < 0.001

RT + TME

overall survival eligible patients n 1809
Overall Survivaleligible patients (n=1809)

TME alone

64.2% vs 63.4%

p = 0.87

RT + TME

dutch trial local recurrence rate level from the anal verge
Dutch trial - Local recurrence rateLevel from the anal verge

0 - 5 cm 6 - 10 cm 11 - 15 cm

10.5% vs 11.9%

p = 0.53

swedish rectal cancer trial
Local recurrence rate (min. 5 years)

(patients operated on for cure)

Preop. irrad . Surgery alone p-value

Ant. res. 9 % (18 / 206) 21 % (41 / 194) < 0.001

Abd. per. 9 % (22 / 243) 25 % (65 / 256) < 0.001

Other op. 33 % ( 2 / 6 ) 38 % ( 3 / 8 )

SWEDISH RECTAL CANCER TRIAL
local recurrence rate
Trial / level Local recurrence

RT - RT + p value

SRCT < 5 cm 27 % 10 % 0.003 TME < 5 cm 11 % 12 %0.53

SRCT 6 - 10 cm 26 % 9 % < 0.001 TME 6 - 10 cm 15 % 4 % < 0.001

SRCT > 10 cm 12 % 8 % 0.3 TME > 10 cm 6 % 4 % 0.15

Local recurrence rate
swedish rectal cancer register1
Data report

1995 - 2004

 15,000 patients ( 1,500 yearly)

Base - line data

Trends in treatment

5-year oncological data

Swedish Rectal Cancer Register
local recurrence 1995 98
Local recurrence % (1995 - 98)

All patients R 0 surgery

rectal cancer treatment what have we learned
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)
preoperative chemo radiotherapy in rectal cancer
Preoperative chemo-radiotherapyin rectal cancer

Is RT/CT superior to RT in resectable rectal cancer ?

Probably, but the evidence is low

Two ! trials are ongoing (EORTC)

(France)

rectal cancer
Non-resectable

Must be identified preop.

Malpractice if not treated with preoperative irradiation

Rectal cancer
non resectable rectal cancer1
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 cancer2
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 cancer3
Uppsala trial 1988 - 96

Prospective randomised trial

46 Gy

vs

40 Gy + MFL

Non-resectable rectal cancer
non resectable rectal cancer4
Uppsala trial 1988 - 96; 3 years follow-up

Irrad. + chemo Irrad. alone

Local recurrence 29 patients 27 patients

All resected patients 3 (10 %) 7 (26 %)

Curative resection 3 (12 %) 7 (30 %)

Local control 26 (89 %) 20 (74 %)

Non-resectable rectal cancer
non resectable rectal cancer5
Uppsala trial 1988 - 96; 3 years follow-up

Irrad. + chemo Irrad. alone

Survival 34 patients 36 patients

Alive 12 (35 %) 8 (22 %)

Median follow-up 62 months 53 months

Dead 22 (65 %) 28 (78 %)

Median survival 27 months 21 months

Non-resectable rectal cancer
non resectable rectal cancer6
Uppsala trial 1988 - 96

Conclusion

The trial was under-powered

Chemo-radiotherapy more toxic

A trend favouring irrad. + MFL

Non-resectable rectal cancer
non resectable rectal cancer7
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)

non resectable rectal cancer8
LARCS

Nordic prospective randomised trial

50 Gy (during 5 weeks)

vs

50 Gy + 5-FU / Lv

Non-resectable rectal cancer
non resectable rectal cancer9
Non-resectable rectal cancer

Preop. prolonged chemo - radiotherapy

40 - 70 %resectable

20 - 30 %long-term cure

adjuvant radiotherapy2
Rectal cancer

Sphincter preservation

A myth or reality ?

Adjuvant radiotherapy
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
the lyon r90 01 trial1
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
the lyon r90 01 trial2
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

The Lyon R90-01 Trial
cao aro aio trial in germany
Trial design

Preop. chemorad.

Postop. chemorad.

CAO/ARO/AIO - trial in Germany

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cao aro aio trial in germany1
Down staging

Preop. chemorad. Postop. chemorad.

No tumour 8 % -

Stage I 26 % 18 %

Stage II 30 % 30 %

Stage III 29 % 43 %

Stage IV 6 % 8 %

CAO/ARO/AIO - trial in Germany
cao aro aio trial in germany3
Overall Survival

N Engl J Med 2004; 351: 1731-40

CAO/ARO/AIO - trial in Germany
cao aro aio trial in germany4
Sphincter preservation

Preop. Postop.

chemorad. chemorad.

Preserved spincters 26/75 35 % 13/74 18 %

Total material 69 % 71 %

CAO/ARO/AIO - trial in Germany
eortc 22921 1011 patients
Trial design

Preop. Radiotherapy

45 Gy

Preop. chemorad.

45 Gy + 5-Fu/Lv

EORTC 22921 (1011 patients)

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eortc 22921 1011 patients1
Down staging

Preop. irrad. Preop. chemorad.

Path. compl. resp 14 % 5.3 %

p < 0.001

EORTC 22921 (1011 patients)
eortc 22921 1011 patients2
Sphincter preservation

Preop. irrad. Preop. chemorad.

Ant. resection 55.6 % 52.4 %

p = 0.05

EORTC 22921 (1011 patients)
ffcd 9203 762 patients
Trial design

Preop. Radiotherapy

45 Gy

Preop. chemorad.

45 Gy + 5-Fu/Lv

FFCD 9203 (762 patients)

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ffcd 9203 762 patients1
Down staging

Preop. irrad. Preop. chemorad.

Path. compl. resp 11 % 3 %

p = 0.05

FFCD 9203 (762 patients)
ffcd 9203 762 patients2
Sphincter preservation

Preop. irrad. Preop. chemorad.

Ant. resection 52 % 52 %

p > 0.05

FFCD 9203 (762 patients)
sphincter preservation polish trial
Trial design

Preop. chemorad. 25 x 2 Gy

Preop. radiotherapy 5 x 5 Gy

Sphincter preservation - Polish trial

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sphincter preservation polish trial1
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 polish trial2
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
adjuvant radiotherapy3
Rectal cancer

Sphincter preservation

Still a myth ?

Adjuvant radiotherapy
neo adjuvant radiotherapy2
Rectal cancer

No preop. radiotherapy

Stage I tumours i.e. uT 1 or uT 2

Rectal Ultrasound very good

Neo - adjuvant radiotherapy
neo adjuvant radiotherapy3
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
neo adjuvant radiotherapy4
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
neo adjuvant radiotherapy5
To whom ?

Large bulky tumour

Narrow male pelvis

Tumours growing anteriorly

Abdominoperineal excision

Neo - adjuvant radiotherapy
neo adjuvant radiotherapy6
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
neo adjuvant radiotherapy7
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
neo adjuvant radiotherapy8
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 % !

Neo - adjuvant radiotherapy
rectal cancer 2005
Conclusion

Appropriate staging !

Consider radiotherapy !

Well trained surgeon !!

Chemotherapy ?

Rectal Cancer 2005
slide92

Colorectal Tripartite Meeting

Royal Dublin Society

5th-7th July 2005

Further details from www.tripartite.org.uk

Closing date for abstracts 10th December 2004