Dept Surgery, Colorectal unit University Hospital, Uppsala, Sweden 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

Transanal Endoscopic Microsurgery 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

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%) 1/38 (3%) p < 0.001 Quirke et al. Lancet, nov 1; 1986

Hardly ever extend more than 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 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 surgery Nodal involvement Proximal Lateral Distal

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

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

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

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

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

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

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 !

Abdominoperineal Excision 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 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 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 Local recurrence RT - RT + ‘sloppy’ 30 % 10 % TME 13 % 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) TME alone 5.8% vs 11.4% p < 0.001 RT + TME

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

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

Dutch trial - Local recurrence rate Level 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 )

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 Register Data 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

Local recurrence % (1995 - 1997) 0 - 6 cm 7 - 15 cm

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 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 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 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 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 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. 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

CAO/ARO/AIO - trial in Germany 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 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. 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 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

EORTC 22921 (1011 patients) Down staging Preop. irrad. Preop. chemorad. Path. compl. resp 14 % 5.3 % p < 0.001

Sphincter preservation 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 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

FFCD 9203 (762 patients) Down staging Preop. irrad. Preop. chemorad. Path. compl. resp 11 % 3 % p = 0.05

Sphincter preservation 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 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

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 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 2005 Conclusion 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