Rectal Cancer - 2005

M62 Coloproctolgy course, Huddersfield

Lars PåhlmanDept Surgery, Colorectal unitUniversity 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 surgeryTwo main options

Local excision Abdominal resection

TEM surgery - adenomas

Transanal Endoscopic

Microsurgery

Full thickness excision

Up to 20 cm Perfect view

Rectal cancer surgeryLocal excision

T 1 tumours ‘Early’ T 2 tumours ‘Any T’ fragile patients TEM - technique crucial

Rectal cancer surgeryLocal tumour control

Mesorectum Lateral spread Intramural spread Implantation metastases Nodal involvement

Rectal Cancer - focus on surgery

Standard surgery

TME

the gold standard

Rectal cancer surgeryLateral 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 surgeryIntramural spread

Hardly ever extend more than

0.5 cm

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

Swedish Rectal Cancer Register5 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 < 0.001 n.s.

Rectal cancer surgeryNodal involvement

Proximal Lateral Distal

Rectal cancer surgeryProximal 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 clearanceSuper 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 clearanceSuper radical surgery

Positive nodes indicates disseminated disease

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

Rectal cancer surgery

Lateral lymph node clearanceMorbidity

Impotence > 60 % Voiding problem > 40 % Prolongs surgery

Rectal cancer surgery

Lateral lymph node clearanceThe 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 clearanceTotal Mesorectal Excision

In all cases ? What is the upper limit ? Morbidity increased !

Rectal cancer surgery

Low rectal cancersAbdominoperineal Excision

Very difficult surgery ! Important to have correct strategy Avoid ‘coning’ ! Start early from below !

Rectal cancer surgeryConclusion

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

22 trials, 8 507 patients Reduction in

overall colorectal isolatedmortality cancer deaths local recurr.

Preoperative:

BED <20 Gy ns ns ns20 - 30 Gy ns ns 24 ± 1530 - 37.5 Gy 10±5* 22 ± 5**** 57 ± 7****

Postoperative:

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

Meta-analysis rectal cancer radiotherapy

Radiotherapy in resectable cancerConclusions from the meta-analysis

Radiotherapy works (with standard surgery)lowers local failure ratesimproves 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 Local recurrence

RT - RT +

‘sloppy’ 30 % 10 %

TME 13 % 6 %

Adjuvant radiotherapyRadiation schedule

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

Accelerated fractionation:25 Gy in 1 week

Adjuvant radiotherapyOngoing 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)

5.8% vs 11.4% p < 0.001

Years since surgery

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TME alone

RT + TME

Overall Survival eligible patients (n=1809)

Years since surgery

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64.2% vs 63.4% p = 0.87

TME alone

RT + TME

Cancer specific survival eligible patients (n=1809)

76.1% vs 73.0% p = 0.18

Years since surgery

86420

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Dutch trial - Local recurrence rate

Level from the anal verge

10.5% vs 11.9% p = 0.53

Years since surgery

86420

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86420

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

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 )

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

Swedish Rectal Cancer RegisterData report

1995 - 2004

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

0 1 2 3 4 5

Överlevnadstid (år)

0

2

4

6

8

10

12

Ej preoperativ strålbehandling (1495 pat)Preoperativ strålbehandling (1353 pat)

0 1 2 3 4 5

Överlevnadstid (år)

0

2

4

6

8

10

12

Ej preoperativ strålbehandling (1981 pat)Preoperativ strålbehandling (1597 pat)

Local recurrence % (1995 - 1997)

0 - 6 cm 7 - 15 cm

7 rec

34 rec

1 rec11 rec

34 rec

1 rec

0

2

4

6

8

10

12

14

16

Främre resektion Abd.amp. Hartmann

Preoperativ strålbehandling Ej preoperativ strålbehandling

33 rec

4 rec

72 rec

4 rec

7 rec

0

2

4

6

8

10

12

14

16

Främre resektion Abd.amp. Hartmann

Preoperativ strålbehandling 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 radio-therapy on an individual level)

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)

Non - Resectable Rectal Cancer

Rectal cancerNon-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 cancerUppsala trial 1988 - 96

Prospective randomised trial

46 Gy

vs

40 Gy + MFL

Non-resectable rectal cancerUppsala 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 cancerUppsala 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 cancerUppsala 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 non-resectable 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

Preop. chemorad.

Postop. chemorad.

Randomisation

Local

Recurr

Survival

CAO/ARO/AIO - trial in GermanyDown 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 GermanyLocal recurrence rate

N Engl J Med 2004; 351: 1731-40

CAO/ARO/AIO - trial in GermanyOverall Survival

N Engl J Med 2004; 351: 1731-40

CAO/ARO/AIO - trial in Germany

Sphincter preservation

Preop. Postop.

chemorad. chemorad.

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

Total material 69 % 71 %

EORTC 22921 (1011 patients)

Trial design

Preop. Radiotherapy

45 Gy

Preop. chemorad.

45 Gy + 5-Fu/Lv

Randomisation

Local

Recurr

Survival

EORTC 22921 (1011 patients)

Down staging

Preop. irrad. Preop. chemorad.

Path. compl. resp 14 % 5.3 %

p < 0.001

EORTC 22921 (1011 patients)

Sphincter preservation

Preop. irrad. Preop. chemorad.

Ant. resection 55.6 % 52.4 %

p = 0.05

FFCD 9203 (762 patients)

Trial design

Preop. Radiotherapy

45 Gy

Preop. chemorad.

45 Gy + 5-Fu/Lv

Randomisation

Local

Recurr

Survival

FFCD 9203 (762 patients)

Down staging

Preop. irrad. Preop. chemorad.

Path. compl. resp 11 % 3 %

p = 0.05

FFCD 9203 (762 patients)

Sphincter preservation

Preop. irrad. Preop. chemorad.

Ant. resection 52 % 52 %

p > 0.05

Sphincter preservation - Polish trial

Trial design

Preop. chemorad. 25 x 2 Gy

Preop. radiotherapy 5 x 5 Gy

Randomisation

Local

Recurr

Survival

Sphincter

preserv

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 RT/CT N = 156

61 % 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 radiotherapyRectal cancer

No preop. radiotherapy

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

Rectal Ultrasound very good

Neo - adjuvant radiotherapyRectal 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 radiotherapyRectal cancer

Neo adjuvant chemo - radiotherapy

Large tumours i.e. advanced T 3 and T 4

Rectal Ultrasound not good

MRI best

Neo - adjuvant radiotherapyTo whom ?

Large bulky tumour

Narrow male pelvis

Tumours growing anteriorly

Abdominoperineal excision

Neo - adjuvant radiotherapyWhy 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 radiotherapyRadiation 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 radiotherapyConclusion

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 2005Conclusion

Appropriate staging !

Consider radiotherapy !

Well trained surgeon !!

Chemotherapy ?

Colorectal Tripartite Meeting

Royal Dublin Society 5th-7th July 2005

Further details from www.tripartite.org.uk

Closing date for abstracts 10th December 2004