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Gastrointestinal Cancer
R. Zenhäusern
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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
cancer death
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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
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Decreasing mortality of CRC
5-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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TisTis TT11 TT22 TT33 T T44
ExtensionExtensionto an adjacentto an adjacent
organorgan
MucosaMucosaMuscularis mucosaeMuscularis mucosae
SubmucosaSubmucosa
Muscularis propriaMuscularis propria
SubserosaSubserosa
SerosaSerosa
TNM Classification
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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
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Adjuvant Chemotherapy of 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/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
bab
ilit
y o
f s
urv
ival
Pro
bab
ilit
y o
f s
urv
ival
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
bab
ilit
y o
f s
urv
ival
Pro
bab
ilit
y o
f s
urv
ival
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
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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 small
cancer 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 number of local recurrences
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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
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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 the results of three randomised trials
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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
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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 of 5-FU is superior to bolus 5-FU during radiotherapy
O`Connell. NEJM 1994;331:331
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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
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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
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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
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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%
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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)
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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 pelvis in all patients, RT may eradicate th remaining ones
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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
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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%
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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
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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 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
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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
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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/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
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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
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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 to
adenocarcinoma decreased from 2:1 (1988) to 1.2:1 (1994)
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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%
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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
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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
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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
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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/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
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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 mo3y 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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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