Gastrointestinal Cancer R. Zenhäusern

Rectal Cancer

Anatomic Location of CRC Cecum14 % Ascending colon10 % Transverse colon12 % Descending colon7 % Sigmoid colon25 % Rectosigmoid junct.9 % Rectum23 % 70%

Epidemiology Increasing Incidence of CRC Incidence / / year >70 y. of age 300 / / year third most common malignant disease second most common cause of cancer death

Epidemiology 1998: 4000 new cases in Switzerland More than 350 women an 600 men die each year due to CRC 70% of CRC are resectable at diagnosis Mortality has decreased

Decreasing mortality of CRC 5-year Survival Colon cancer40-45% 60% Rectal cancer35-40% 58%

WHO Classification of CRC Adenocarcinoma in situ / severe dysplasia Adenocarcinoma Mucinous (colloid) adenocarcinoma (>50% mucinous) Signet ring cell carcinoma (>50% signet ring cells) Squamous cell (epidermoid) carcinoma Adenosquamous carcinoma Small-cell (oat cell) carcinoma Medullary carcinoma Undifferentiated Carcinoma

TNM Primary Lymph-node DistantDukes stage tumor metastasis metastasisstage Stage 0TisN0M0AA Stage IT1N0M0AA1 T2N0M0AB1 Stage IIT3N0M0BB2 T4N0M0BB2 Stage III Aany TN1M0CC1/C2 Bany TN2, N3M0CC1/C2 Stage IVany Tany NM1DD Astler-Coller modified Dukes stage Clinical Staging of CRC

TisT 1 T 2 T 3 T 4 Extension to an adjacent organ Mucosa Muscularis mucosae Submucosa Muscularis propria SubserosaSerosa TNM Classification

Stage and Prognosis Stage5-year Survival (%) 0,1 Tis,T1;No;Mo > 90 I T2;No;Mo II T3-4;No;Mo III T2;N1-3;Mo III T3;N1-3;Mo III T4;N1-2;Mo IV M1 <3

Adjuvant Chemotherapy of Colon Cancer Therapy relapse-free Overall 5-year Survival Survival Surgery62 % 78 % Surgery71 % 83 % + 6x 5-FU/Lv

22% reduction in death35% reduction of recurrence The IMPACT analysis for stages B and C disease 1 5FU= mg/m 2 D1 to D5 + FA 200 mg/m 2 D1 to D5 (every 28 days — 6 cycles) n=736 Control n= Stage B Stage C Time from randomization (years) Probability of survival Patients at risk Control, Stage B Fluorouracil/folinic acid Stage B Control, Stage C Fluorouracil/folinic acid Stage C Overallsurvival Stage B Stage C Time from randomization (years) Probability of survival Patients at risk Control, Stage B Fluorouracil/folinic acid Stage B Control, Stage C Fluorouracil/folinic acid Stage C Overallsurvival 1 IMPACT investigators. Lancet.1995;345: Adjuvant chemotherapy of colon cancer

Purpose of Radio(chemo)therapy in Rectal Cancer To lower local failure rates and improve survival in resectable cancers to allow surgery in primarly inextirpable cancers to facilitate a sphincter-preserving procedure to cure patients without surgery: very small cancer or very high surgical risk

Rectal Cancer Surgery is the mainstay of treatment of RC After surgical resection, local failure is common Local recurrence after conventional surgery: 15%-45% (average of 28%) Radiotherapy significantly reduces the number of local recurrences

Radiotherapy in the management of RC In at least 28 randomised trials the value of either preoperative or postoperative RT has been tested Preoperative RT (30+Gy): 57% relative reduction of local failure Postoperative RT (35+Gy): 33% relative reduction Colorectal Cancer Collaborative Group. Lancet 2001;358:1291 Gamma C. JAMA 2000;284:1008

Adjuvant Therapy of Rectal Cancer 1990 US NIH Consensus Conference Postoperative chemoradiotherapy = standard of care for RC Stage II,II The consensus statement was based upon the results of three randomised trials

Postoperative radiochemotherapy GITSGNCCTGNSABP-R01 Number of pts Surgery aloneLF (%)2425 S (%)4343 RadiotherapyLF (%) S (%) ChemotherapyLF (%)2721 S (%)2153 Chemoradioth.LF (%) S (%)5958

ESMO Recommendations Resectable cases Surgical procedure: TME Preoperative RT: recommended Postoperative chemoradiotherapy: T3,4 or N+ Non-resectable cases: local recurrences Preoperative RT with or without CT

Optimal combination of chemo- radiotherapy? If radiochemotherapy is used postoperatively, protacted infusion of 5-FU is superior to bolus 5-FU during radiotherapy O`Connell. NEJM 1994;331:331

Protacted Infusion of 5-FU 660 patients with stage II,III rectal cancer PI-FUBo-FU Local recurrencensns p= year DFS63%53% p= year OS70%60% p=0.005 O`Connell. NEJM 1994;331:331

Preoperative RT in resectable RC Swedish Rectal Cancer Trial 1168 patients randomised to 25 Gy (5x5) PRT or no RT Surgery alonePreop. RT Rate of local recurrence27%11% p< year overall survival48%58% p=0.004 Swedish Rectal Cancer Trial. NEJM 1997;336:980

Predicting risk of recurrence in RC Surgery-related -Low anterior resection -Excision of the mesorectum -Extend of lymphadenectomy -postoperative anastomotic leakage -Tumor perforation Tumor-related -Anatomic location -Histologic type -Tumor grade -Pathologic stage -radial resection margin -neural, venous, lymphatic invasion

Incidence of local failure in RC T1-2,No,Mo<10% T3,No,Mo15-35% T1,N1,Mo15-35% T3-4,N1-2,Mo45-65%

Total Mesorectal Excision (TME) Local recurrence rates after surgical resection of RC have decreased from about 30% to < 10% 1. Radio(chemo)therapy 2. Importance of circumferential margin (TME)

Total Mesorectal Excision (TME) TME series with local recurrence rates of 5% Other series report recurrence rates of 5-15% Inclusion of patients with T1-2,No disease Experience of the surgeon is important Higher complication rates TME will not remove all tumor cells in the pelvis in all patients, RT may eradicate th remaining ones

TME +/- preoperative RT Dutch Colorectal Cancer Group 1861 patients randomised TME vs PRT+TME TMEPRT+TME Recurrence rate2.4%8.2% OSnsns Kapiteijn E. NEJM 2001;345:638

Preoperative therapy for sphincter preservation Phase II data with no randomised trials Optimal regimen not known Long-term functional outcome? Five of seven trials report sphincter preservation in approximately 75%

Preoperative Therapy in locally advanced/non-resectable rectal cancer Favourable treatment results in phase II trials with preoperative radiochemotherapy Chemoradiotherapy was viewed as standard based on phase II data

Preoperative vs. Postoperative chemoradiotherapy for rectal cancer Randomized trial of the German Rectal Cancer study Group: Sauer R et al. N Engl J Med 2004;351: cT3 or cT4 or node-positive rectal cancer 50,4 Gy (1.8 Gy per day) 5-FU: 1000 mg/m 2 per day (d1-5) during 1. and 5. week

Preoperative vs. Postoperative chemoradiotherapy for rectal cancer Preop CRTPostop CRT PatientsN=415N=384 5 y. OS76%74%p=0.8 5 y. local relapse6%13%p=0.006 G3,4 toxic effects27%40%p=0.001 Increase in sphincter-preserving surger<y with preop Th. Sauer R et al. N Engl J Med 2004;351:

Capecitabine in combination with preoperative radiotherapy Phase I/II studies demonstrate that capecitabine is effective and well tolerated in combination with preoperative radiotherapy Capecitabine 825 mg/m 2 twice daily given continously with standard RT can be recommended Phase II trials are ongoing PETACC-6: capecitabine + RT vs. Capecitabine +Oxalipaltin +RT R. Glynne-Jones. Annals of Oncology 2006;17:

Capecitabine in combination with preoperative radiotherapy Phase II study in locally advanced rectal cancer 53 pat. with T3, N0-2, T4, N0-2 cancer Capecitabine 825 mg/m 2 twice daily for 7 days/week and concomitant RT (50.4 Gy/28 fractions) Overall response:58% Downstaging rate:57% Pathological CR:24% Sphincter-saving Op:59% (20/34 pat. <5cm ) A.De Paoli et al. Annals of Oncology 2006;17:

Chemotherapy with preoperative radiotherapy in rectal cancer Adding fluorouracil-based chemotherapy to preoperative or postoperative RT has no significant influence on survival. Chemotherapy before or after surgery, confers a significant benefit with respect to local control. Bosset JF et al. N Engl J Med 2006;355:

Esophageal Cancer

Lifetime risk: 0.8% for men, 0.3% for women Mean age at diagnosis 67 years Sixth leading cause of death from cancer Overall incidence: 5 / persons Relative incidence of squamous-cell to adenocarcinoma decreased from 2:1 (1988) to 1.2:1 (1994)

Surgery for Esophageal cancer Five-year survival after complete surgical removal of the tumor: Stage 0:95% Stage I:50-80% Stage IIA:30-40% Stage IIB:10-30% Stage III:10-15%

Preoperative RT for Esophageal cancer Five randomized trials (>100 pat.) have compared preoperative RT with immediate surgery Total dose of RT: 20 – 40 Gy None of the studies demonstrated a survival advantage Arnott SJ et al. Int J Radiat Oncol Biol Phys 1998;41:

Preoperative CT for Esophageal cancer A randomized US study (N=440) showed no benefit: 3 cycles cisplatin / fluorouracil 2y survival 35% vs 37% Kelsen et al. N Engl J Med 1998;339: A randomized British study (N=802) suggested an increase in survival 2 y survival 43% vs 34% MRC Oesophageal Cancer Working Group. Lancet 2002;359:

Preoperative CT and RT for Esophageal cancer Eight randomized trials ( seven negativ, one showed a benefit) StudyNCTRTMS3yS (mo)(%) Le Prise /45C/F20 Gy10/109/17 Apinop /35C/F40 Gy7/1020/26 Walsh /58C/F40 Gy11/166/32 Bosset /143 C37 Gy19/1937/39 Urba /50CVF40 Gy18/1716/30 Burmeister /128 C/F35 Gy22/19

Nonsurgical CT and RT Cisplatin / Fluorouracil and RT (50 Gy) Long-term survival in approximately 25 % Increasing the radiation dose was unsuccessful Minsky BD et al. J Clin Oncol 2002;20:

Gastric Cancer

9.9% of all new cancer diagnosis 12% of all cancer deaths Overall 5 y. survival 15%-35% Declining incidence in the West

Surgery for Gastric Cancer Stage I:5y survival 58%-78% Stage II:5y survival 34% Local or regional recurrence after gastric resection with curative intent: 40-65% Adjuvant chemoradiotherapy ?

CRT after surgery vs. surgery alone Randomized trial n=556, T1-4, No-2 Resected adenocarcinoma of the stomach or gastroesophageal junction 1 cycle leucovorin 20mg/m 2, Fluorouracil 425 mg/m 2 day 1-5 RT 45 Gy (1.8Gy per day), beginning on day 28 Lv 20mg/m 2, FU 400 mg/m 2 d. 1-4 and last 3 d. of RT 2 cycles leucovorin 20mg/m 2, Fluorouracil 425 mg/m 2 day 1-5 MacDonald et al. N Engl J Med 2001;345:

CRT after surgery vs. surgery alone Results:CRTSurgery 3y survival50%41% p=0.005 Med. OS36 mo27 mo 3y RFS48%31% Local reccurence19%29% MacDonald et al. N Engl J Med 2001;345:

Perioperative chemotherapy vs. surgery alone Randomized trial: n=503 Chemotherapy: 3 preoperative and 3 postoperative cycles Epirubicin 50mg/m 2, cisplatin 60mg/m 2, day1 Fluorouracil cont i.v. 200mg/m 2, day 1-21 Cunningham et al. N Engl J Med 2006;355:11-20

Perioperative chemotherapy vs. surgery alone Results: CTSurgery 5y OS 36.3% 23% Local recurrence 14.45% 20.6% Cunningham et al. N Engl J Med 2006;355:11-20