Radiotherapy for Colo-rectal Cancer

Case 1

ס"ם מפי הטבעת9 גידול בגובה 58בן •

קולונוסקופיה – גידול צירקולרי, כמעט חוסם•

• TRUS T3 N0

TMEמועמד לניתוח •

טיפול??•

Staging

• Clinical– Rectal exam + rectoscopy– TRUS– Abdomino-pelvic CT– Chest X-ray– CEA?

• Pathological

Aim of adjuvant chemo-radiation

• 1o aim – overall survival• 2o aim - Loco-regional control

- Disease free survival

- Quality of life• Sphincter preservation

– Down-staging

• Long-term bowel function• Urinary function• Sexual function

Endoscopic ultrasound

Surgical Procedures for Rectal Cancer

• Radical– Abdominoperineal resection– Low anterior resection– Proctectomy and coloanal anastomosis– Total mesorectal excision

• Conservative– Transanal excision– Transanal endoscopic microsurgery

• Ablative procedures– Endoscopic laser Fulguration– Brachytherapy

Mesorectal resection

Low coloanal anastamosis

Radiotherapy for colo-rectal cancer• Rationale

– Local control– Survival– Down-staging

• Indications– Risk of local recurrence >10%– Radiotherapy can be safely delivered to site of highest risk

• Sites– Rectum– Cecum– Other sites - T4

Patterns of failure rectal cancer

• Pelvic failure rate– B2-C1 - 10-60% – C2 - 30-70%

• Patients undergoing 2nd look operation– Pelvic recurrence 92 % – Pelvic recurrence only 48% Gunderson 1974

Adjuvant radiotherapy for rectal cancer: a

systematic overview of 8,507 patients from 22

randomised trials. Lancet 2001;358:1291

risk of death from non-rectal cancer

causes and from rectal cancer from six trials

of preoperative radiotherapy

(biologically effective dose >30 Gy)

MRI evaluation of tumor response Sauer

Systematic overview Lancet 358:1291, 2001 radiotherapy dose-response

reduced death rate increased reduced

BED overall cancer specific non-cancer death local failure

Pre-op• <20 Gy 6% 11% 5% -20%• 20-30 Gy 1% 1% 15% 24%• >30 Gy 10% 22% 37% 57%

All pre-op 6% 13% 15% 46%

Post-op >35 Gy 5% 9% 12% 37%

Mesorectal resection

Rates of Overall Survival in 1805 Eligible Patients, TME study

TME study: local recurrence 2 years after complete resection2.4% in XRT & surgery and 8.2% in surgery alone (P<0.001)

Sphincter preservation

• Pre 1990 – 95% pts with low <6 cm tumors underwent AP

resection

• Post 1990: Pre-op XRT– Several series 80% sphincter preservation– 85-90% local control (3-4 yrs)– 75-90% good bowel function

Adjuvant radiotherapy for rectal cancer pre-operative

postoperative

• Staging clinical surgical

• Toxicity less more– Bowel may be trapped after surgery

• Surgery down-stagingreduced spillage

Relative reduction in local failure according to number of 5 Gy fractions. Size of symbols is proportional to the number of patients in trial. The 3 large trials are, from the top, te TME trial, Swedish Rectal Cancer trial and the Stockholm I trial.

Dose (5Gy fx studies)

Radiotherapy toxicity 5 Gy x 5 pre-op

• Stockholm trials– Trial 1 large AP/PA fields 8% post-op mortality (Cancer 66:49, 1990)

• 1 & 2 combined (Cancer 78:968, 1996)

– Thromboembolism RR 2– Pelvic/femoral fractures RR 3– Intestinal obstruction RR 1.5– Fistula RR 2.8

• Swedish trial (Dis Colon Rectum 41:543 1998)

– > 4 stools per day 20%– Emptying difficulties 52%– Incontinence of loose stool 50%

Radiotherapy volumes in trials using 5 * 5 Gy and postoperative mortality

Volume technique Energy given (J)

• Stockholm(+) Mid L2 2-beams 310• Uppsala Mid L3 3-beams 210–

250• SRCT Mid L4 3/4 beams 190• Stockholm II (+) (As SRCT, but no shields) 270• TME Mid L5 3/4 beams 140–170

Small bowel sparing using high-energy linear accelerator XRT

prone three-field treatment v AP/PA.

The small bowel (arrows) remains fixed in the pelvis, and cannot be excluded from the lateral fields.

Post-operative radiotherapy

The small bowel (arrows) is excluded from the lateral fields Note: place wire to exclude perineum or use anal marker

Pre-operative radiotherapy

Correlation between the volume of small bowel receiving 15 Gy (V15) and degree of acute small

bowel toxicity Baglan KL Int J Radiat Oncol Biol Phys 2002 52:176

  .

Adjuvant versus Neoadjuvant Chemo-radiation for Rectal Cancer: Sauer NEJM 2004

• Phase III preop 45 Gy CRT v postop 45 Gy CRT

• Eligibility: T3/T4 or N+• 5−FU (1g/m2/d - 120h−CI) 1st and 5th week of XRT • Interval between CRT and surgery was 4−6 weeks• Techniques of surgery standardized and included TME

– Stratification was done according to surgeon

• 797 evaluable patients in 26 institutions

Adjuvant versus Neoadjuvant Chemo-radiation for Rectal Cancer: Sauer NEJM 2004

• Post-op Pre op

• 5−year pelvic recurrence 11% 7% (p = 0.02)

– 5−year distant recurrence 34% 30% (p = 0.52)

– disease−free survival 55% 59% (p = 0.23) – overall−survival 73% 78% (p =0.38)

• chronic anastomotic stenosis 8.5% 2.7% (p = 0.001)

– Acute grade 3 and 4 toxicity 31.7% 28.8% (p -n.s.)

• sphincter preservation 19% 39% (p = 0.004)– subgroup of 188 patients with low−lying tumors declared by surgeon prior to

randomization to require an AP resection

Adjuvant versus Neoadjuvant Chemo-radiation for Rectal Cancer: German Study

Sauer ASTRO 2003; local recurrence

Pre-operative 5-FU chemoradiation: commonly used in rectal cancer

• 5-FU-based chemoradiation has become part of pre-operative therapy for rectal cancer– More effective downstaging than XRT alone

• Historical controls

• Pivotal EORTC study now completed accrual

– 10–30% pCR rates

• With postoperative XRT protracted infusion of 5-FU improves survival versus bolus 5-FU

1O’Connell MJ et al. N Engl J Med 1994;331:502–7

EORTC study

Newer drugs in chemo-radiation of rectal cancer

• Indications:– Locally advanced T4– N+– May be overkill for T2-T3 N0

• Drugs– Oxaliplatin– Irinotecan (CPT-11)– Bevacizumab– EGFR inhibitors

NSABP R-04 rectal cancer trial

*Plus 5.4Gy for fixed tumours

Resectable rectal cancer, stage II–III

n=1 600

Capecitabine continuous throughout radiotherapy (50.4Gy*)

SURGERY

5-FU continuous infusion throughout

radiotherapy (50.4Gy*)

• Objectives – DFS– Recurrence rate– pCR– safety

Direct evidence that the VEGF-specific antibody bevacizumab

has antivascular effects in human rectal cancer. Willett Nat Med 2004

Case 2

עצירות כרונית54בת •

ס"ם מפי הטבעת (מעל 3גידול בגובה •הספינקטר)

•TRUS T2 N0

מסרבת כריתה ראדיקאלית•

טיפול??•

Sphincter preservation local therapy only

• Endocavity radiation Local failure – T1 3%– T2 33%– Local excision only– T1 0-33%– T2 0-43%– Local excision & XRT– T1 0-10%– T2 0-18%

Candidates for local therapy of rectal cancer

• Indications– Tumor <3 cm– Well differentiated– Submucosa or superficial muscularis

• Options– Transanal resection– Brachytherapy– External beam radiotherapy

Local therapy only – what about lymph nodes?

• Incidence of peri-rectal lymph nodes– T1 0-12%– T2 22-28%– T3 36%– Grade 1 0-4%– Grade 2 14-30%– Grade 3 50%