Gastrointestinal Cancer R. Zenhäusern

Rectal Cancer

Anatomic Location of CRC Cecum 14 % Ascending colon 10 % Transverse colon 12 % Descending colon 7 % Sigmoid colon 25 % Rectosigmoid junct.9 % Rectum 23 % 70%

Epidemiology Increasing Incidence of CRC Incidence 30-40 / 100000 / year >70 y. of age 300 / 100000 / 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 1960-70 1980-90 Colon cancer 40-45% 60% Rectal cancer 35-40% 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

Clinical Staging of CRC Astler-Coller modified Dukes stage TNM Primary Lymph-node Distant Dukes stage tumor metastasis metastasis stage Stage 0 Tis N0 M0 A A Stage I T1 N0 M0 A A1 T2 N0 M0 A B1 Stage II T3 N0 M0 B B2 T4 N0 M0 B B2 Stage III A any T N1 M0 C C1/C2 B any T N2, N3 M0 C C1/C2 Stage IV any T any N M1 D D

TNM Classification Extension Tis T1 T2 T3 T4 Mucosa Muscularis mucosae to an adjacent organ Mucosa Muscularis mucosae Submucosa Muscularis propria Subserosa Serosa

Stage and Prognosis Stage 5-year Survival (%) 0,1 Tis,T1;No;Mo > 90 I T2;No;Mo 80-85 II T3-4;No;Mo 70-75 III T2;N1-3;Mo 70-75 III T3;N1-3;Mo 50-65 III T4;N1-2;Mo 25-45 IV M1 <3

Adjuvant Chemotherapy of Colon Cancer Therapy relapse-free Overall 5-year Survival Survival Surgery 62 % 78 % Surgery 71 % 83 % + 6x 5-FU/Lv

The IMPACT analysis for stages B and C disease1 Adjuvant chemotherapy of colon cancer The IMPACT analysis for stages B and C disease1 5FU=370-400 mg/m2 D1 to D5 + FA 200 mg/m2 D1 to D5 (every 28 days — 6 cycles) n=736 Control n=757 22% reduction in death 35% reduction of recurrence Overall survival 1.0 0.8 0.6 0.4 0.2 Stage B Stage C Overall survival 1.0 0.8 0.6 0.4 0.2 Stage B Stage C Probability of survival Probability of survival 0 1 2 3 0 1 2 3 4 Time from randomization (years) Time from randomization (years) Patients at risk Control, Stage B 423 403 327 189 Fluorouracil/folinic acid Stage B 418 399 328 188 Control, Stage C 334 298 225 125 Fluorouracil/folinic acid Stage C 318 300 231 161 Patients at risk Control, Stage B 423 347 256 139 56 Fluorouracil/folinic acid Stage B 418 357 262 140 60 Control, Stage C 334 223 141 69 28 Fluorouracil/folinic acid Stage C 318 250 179 118 42 1IMPACT investigators. Lancet.1995;345:939-944.

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 GITSG NCCTG NSABP-R01 Number of pts. 202 204 555 Surgery alone LF (%) 24 25 S (%) 43 43 Radiotherapy LF (%) 20 25 16 S (%) 52 47 41 Chemotherapy LF (%) 27 21 S (%) 21 53 Chemoradioth. LF (%) 11 14 8 S (%) 59 58

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-FU Bo-FU Local recurrence ns ns p=0.11 4-year DFS 63% 53% p=0.01 4-year OS 70% 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 alone Preop. RT Rate of local recurrence 27% 11% p<0.001 5-year overall survival 48% 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,Mo 15-35% T1,N1,Mo 15-35% T3-4,N1-2,Mo 45-65%

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 TME PRT+TME Recurrence rate 2.4% 8.2% OS ns ns 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;351:1731-40 cT3 or cT4 or node-positive rectal cancer 50,4 Gy (1.8 Gy per day) 5-FU: 1000 mg/m2 per day (d1-5) during 1. and 5. week

Preoperative vs. Postoperative chemoradiotherapy for rectal cancer Preop CRT Postop CRT Patients N=415 N=384 5 y. OS 76% 74% p=0.8 5 y. local relapse 6% 13% p=0.006 G3,4 toxic effects 27% 40% p=0.001 Increase in sphincter-preserving surger<y with preop Th. Sauer R et al. N Engl J Med 2004;351:1731-40

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/m2 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;17:361-371

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/m2 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;17:246-251

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;355:1114-1123

Esophageal Cancer

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 /100000 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;41:579-583

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;339:1979-1984 A randomized British study (N=802) suggested an increase in survival 2 y survival 43% vs 34% MRC Oesophageal Cancer Working Group. Lancet 2002;359:1727-1733

Preoperative CT and RT for Esophageal cancer Eight randomized trials ( seven negativ, one showed a benefit) Study N CT RT MS 3yS (mo) (%) Le Prise 1994 41/45 C/F 20 Gy 10/10 9/17 Apinop 1994 34/35 C/F 40 Gy 7/10 20/26 Walsh 1996 55/58 C/F 40 Gy 11/16 6/32 Bosset 1997 139/143 C 37 Gy 19/19 37/39 Urba 2001 50/50 CVF 40 Gy 18/17 16/30 Burmeister 2002 128/128 C/F 35 Gy 22/19

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;20:1167-1174

Gastric Cancer

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/m2, Fluorouracil 425 mg/m2 day 1-5 RT 45 Gy (1.8Gy per day), beginning on day 28 Lv 20mg/m2, FU 400 mg/m2 d. 1-4 and last 3 d. of RT 2 cycles leucovorin 20mg/m2, Fluorouracil 425 mg/m2 day 1-5 MacDonald et al. N Engl J Med 2001;345:725-730

CRT after surgery vs. surgery alone Results: CRT Surgery 3y survival 50% 41% p=0.005 Med. OS 36 mo 27 mo 3y RFS 48% 31% Local reccurence 19% 29% MacDonald et al. N Engl J Med 2001;345:725-730

Perioperative chemotherapy vs. surgery alone Randomized trial: n=503 Chemotherapy: 3 preoperative and 3 postoperative cycles Epirubicin 50mg/m2, cisplatin 60mg/m2, day1 Fluorouracil cont i.v. 200mg/m2, day 1-21 Cunningham et al. N Engl J Med 2006;355:11-20

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