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Gastrointestinal Cancer

R. Zenhusern

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Rectal Cancer

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Anatomic Location of CRC Cecum 14 %

Ascending colon 10 %

Transverse colon 12 %

Descending colon 7 %

Sigmoid colon 25 %

Rectosigmoid junct.9 % Rectum 23 %

70%

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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 cancerdeath

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Epidemiology 1998: 4000 new cases in Switzerland

More than 350 women an 600 men dieeach year due to CRC

70% of CRC are resectable at diagnosis

Mortality has decreased

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Decreasing mortality of CRC5-year Survival

1960-70 1980-90

Colon cancer 40-45% 60%

Rectal cancer 35-40% 58%

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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

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TNM Primary Lymph-node Distant Dukesstage 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

Astler-Collermodified

Dukes stage

Clinical Staging of CRC

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Tis T1 T2 T3 T4

Extension

to an adjacentorgan

Mucosa

Muscularis mucosae

Submucosa

Muscularis propria

Subserosa

Serosa

TNM Classification

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Stage and Prognosis

Stage 5-year Survival (%)

0,1 Tis,T1;No;Mo > 90

I T2;No;Mo 80-85II T3-4;No;Mo 70-75

III T2;N1-3;Mo 70-75

III T3;N1-3;Mo 50-65III T4;N1-2;Mo 25-45

IV M1

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Adjuvant Chemotherapyof Colon Cancer

Therapy relapse-free Overall

5-year Survival Survival

Surgery 62 % 78 %

Surgery 71 % 83 %

+ 6x 5-FU/Lv

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22% reduction in death 35% reduction of recurrence

The IMPACT analysis for stages B and C disease1

5FU=370-400 mg/m2D1 to D5 + FA 200 mg/m2D1 to D5

(every 28 days6 cycles) n=736

Control n=757

1.0

0.8

0.6

0.4

0.2

0

0 1 2 3

Stage B

Stage C

Time from randomization (years)

Probabilityofsurvival

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

Overall

survival1.0

0.8

0.6

0.4

0.2

0

0 1 2 3 4

Stage B

Stage C

Time from randomization (years)

Probabilityofsurvival

Patients at risk

Control, Stage B 423 347 256 139 56

Fluorouracil/folin ic acid Stage B 418 357 262 140 60

Control, Stage C 334 223 141 69 28

Fluorouracil/folin ic acid Stage C 318 250 179 118 42

Overall

survival

1IMPACT investigators. Lancet.1995;345:939-944.

Adjuvant chemotherapy of colon cancer

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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 smallcancer or very high surgical risk

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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 numberof local recurrences

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Radiotherapy in the management of RC

In at least 28 randomised trials the value of eitherpreoperative or postoperative RT has been tested

Preoperative RT (30+Gy): 57%relative reductionof local failure

Postoperative RT (35+Gy): 33%relative reduction

Colorectal Cancer Collaborative Group. Lancet 2001;358:1291

Gamma C. JAMA 2000;284:1008

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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 theresults of three randomised trials

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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

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Optimal combination of chemo- radiotherapy?

If radiochemotherapy is used

postoperatively, protacted infusion of5-FU is superior to bolus 5-FU duringradiotherapy

O`Connell. NEJM 1994;331:331

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Protacted Infusion of 5-FU660 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

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Preoperative RT in resectable RCSwedish 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

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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

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Total Mesorectal Excision (TME)

Local recurrence rates after surgicalresection of RC have decreased from about30% to < 10%

1. Radio(chemo)therapy

2. Importance of circumferential margin (TME)

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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 pelvisin all patients, RT may eradicate th remainingones

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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

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Preoperative therapy forsphincter 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%

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Preoperative Therapy in locallyadvanced/non-resectable rectal cancer

Favourable treatment results in phase IItrials

with preoperative radiochemotherapy

Chemoradiotherapywas viewed as standard basedon phase II data

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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

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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

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Capecitabine in combination with

preoperative radiotherapy Phase I/II studies demonstrate that capecitabine

is effective and well tolerated in combination withpreoperative radiotherapy

Capecitabine 825 mg/m2twice daily givencontinously 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

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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/m2twice daily for 7 days/weekand concomitant RT (50.4 Gy/28 fractions)

Overall response: 58%

Downstaging rate: 57%

Pathological CR: 24% Sphincter-saving Op: 59% (20/34 pat.

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Chemotherapy with preoperativeradiotherapy in rectal cancer

Adding fluorouracil-based chemotherapy topreoperative or postoperative RT has nosignificant influence on survival.

Chemotherapy before or after surgery, confers asignificant benefit with respect to local control.

Bosset JF et al. N Engl J Med 2006;355:1114-1123

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Esophageal Cancer

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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 toadenocarcinoma decreased

from 2:1 (1988) to 1.2:1 (1994)

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Surgery for Esophageal cancer

Five-year survival after complete surgical removalof the tumor:

Stage 0: 95%

Stage I: 50-80%

Stage IIA: 30-40%

Stage IIB: 10-30%

Stage III: 10-15%

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Preoperative RT for Esophageal cancer

Five randomized trials (>100 pat.) havecompared preoperative RT with immediate

surgery Total dose of RT: 20 40 Gy

None of the studies demonstrated asurvival advantage

Arnott SJ et al. Int J Radiat Oncol Biol Phys 1998;41:579-583

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Preoperative CT for Esophageal cancer

A randomized US study (N=440) showed nobenefit: 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

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Preoperative CT and RTfor 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

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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

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Gastric Cancer

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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

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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 ?

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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/m2day 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/m2day 1-5

MacDonald et al. N Engl J Med 2001;345:725-730

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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

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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

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