1. Gastrointestinal Cancer
R. Zenhäusern

2. Rectal Cancer

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

4. 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

5. 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

6. Decreasing mortality of CRC
5-year Survival
Colon cancer % 60%
Rectal cancer % 58%

7. 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

8. 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

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

10. Stage and Prognosis Stage 5-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

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

12. The IMPACT analysis for stages B and C disease1
Adjuvant chemotherapy of colon cancer
The IMPACT analysis for stages B and C disease1
5FU= 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
Time from randomization (years)
Time from randomization (years)
Patients at risk
Control, Stage B
Fluorouracil/folinic acid Stage B
Control, Stage C
Fluorouracil/folinic acid Stage C
Patients at risk
Control, Stage B
Fluorouracil/folinic acid Stage B
Control, Stage C
Fluorouracil/folinic acid Stage C
1IMPACT investigators. Lancet.1995;345:

13. 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

14. 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

15. 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

16. 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

17. Postoperative radiochemotherapy
GITSG NCCTG NSABP-R01
Number of pts
Surgery alone LF (%)
S (%)
Radiotherapy LF (%)
S (%)
Chemotherapy LF (%)
S (%)
Chemoradioth. LF (%)
S (%)

18. 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

19. 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

20. 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

21. 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

22. 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

23. Incidence of local failure in RC
T1-2,No,Mo <10%
T3,No,Mo %
T1,N1,Mo %
T3-4,N1-2,Mo %

24. 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)

25. 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

26. 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

27. 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%

28. 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

29. 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/m2 per day (d1-5) during 1. and 5. week

30. 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:

31. 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:

32. 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:

33. 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:

34. Esophageal Cancer

35. 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)

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

37. 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:

38. 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:

39. 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 /45 C/F 20 Gy 10/10 9/17
Apinop /35 C/F 40 Gy 7/10 20/26
Walsh /58 C/F 40 Gy 11/16 6/32
Bosset /143 C 37 Gy 19/19 37/39
Urba /50 CVF 40 Gy 18/17 16/30
Burmeister /128 C/F 35 Gy 22/19

40. 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:

41. Gastric Cancer

42. 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

43. 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 ?

44. 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:

45. 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:

46. 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

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