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

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

TisTis TT11 TT22 TT33 T T44

ExtensionExtensionto an adjacentto an adjacent

organorgan

MucosaMucosaMuscularis mucosaeMuscularis mucosae

SubmucosaSubmucosa

Muscularis propriaMuscularis propria

SubserosaSubserosa

SerosaSerosa

TNM Classification

Stage and Prognosis

Stage 5-year Survival (%)

0,1 Tis,T1;No;Mo > 90I T2;No;Mo 80-85II T3-4;No;Mo 70-75

III T2;N1-3;Mo 70-75III T3;N1-3;Mo 50-65

III T4;N1-2;Mo 25-45IV 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

22% reduction in death 35% reduction of recurrence

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

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

00

00 11 22 33

Stage BStage B

Stage CStage C

Time from randomization (years)Time from randomization (years)

Pro

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Patients at riskPatients at risk

Control, Stage BControl, Stage B 423423 403403 327327 189189

Fluorouracil/folinic acid Stage BFluorouracil/folinic acid Stage B 418418 399399 328328 188188

Control, Stage CControl, Stage C 334334 298298 225225 125125

Fluorouracil/folinic acid Stage CFluorouracil/folinic acid Stage C 318318 300300 231231 161161

OverallOverallsurvivalsurvival 1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

00

00 11 22 33 44

Stage BStage B

Stage CStage C

Time from randomization (years)Time from randomization (years)

Pro

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Pro

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Patients at riskPatients at risk

Control, Stage BControl, Stage B 423423 347347 256256 139139 5656

Fluorouracil/folinic acid Stage BFluorouracil/folinic acid Stage B 418418 357357 262262 140140 6060

Control, Stage CControl, Stage C 334334 223223 141141 6969 2828

Fluorouracil/folinic acid Stage CFluorouracil/folinic acid Stage C 318318 250250 179179 118118 4242

OverallOverallsurvivalsurvival

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

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

GITSG NCCTGNSABP-R01

Number of pts. 202 204 555

Surgery alone LF (%) 24 25S (%) 43 43

Radiotherapy LF (%) 20 25 16S (%) 52 47 41

Chemotherapy LF (%) 27 21S (%) 21 53

Chemoradioth. LF (%) 11 14 8S (%) 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 recurrence27% 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 anastomoticleakage

-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

TMEPRT+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 CRTPostop 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 mo3y 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