Maag - UZ Brussel

Laarbeeklaan 101 – 1090 Brussel
Oncologisch Handboek
Richtlijnen Digestieve Oncologie
Maag
V3.15
Oncologisch Handboek
UZ Brussel
Maag – ICD-O C16
Volgende subregio’s worden beschreven:
1. Fundus (C16.1)
2. Corpus (C16.2)
3. Antrum (C16.3) en pylorus (C16.4)
1.
Classificatie (UICC TNM Classification of Malignant Tumors;
Seventh edition)
Tx
T0
Tis
T1
= oordeel over primaire tumor niet mogelijk
= geen primaire tumor
= carcinoma in situ/hooggradige dysplasie
= invasie van de lamina propria, muscularis mucosae of submucosa
T1a= lamina propria of muscularis mucosae
T1b= submucosa
T2 = invasie van de muscularis propria
T3 = invasie van de subserosa
T4 = tumor perforeert de serosa of invadeert de omliggende structuren
T4a= tumor perforeert serosa
T4b= tumor invadeert omliggende structuren*
Nx
N0
N1
N2
N3
= oordeel over regionale lymfeklieren niet mogelijk
= geen regionale lymfekliermetastasen
= metastasen in 1-2 regionale lymfeklieren
= metastasen in 3-6 regionale lymfeklieren
= metastasen in 7 of meer regionale lymfeklieren
N3a= metastasen in 7-15 regionale lymfeklieren
N3b= metastasen in 16 of meer regionale lymfeklieren
M0 = geen metastasen op afstand
M1 = metastase(n) op afstand
*
Omliggende strcturen van de maag: milt, colon transversum, diafragma, lever, pancreas,
abdominale wand, bijnieren, nieren, dunne darm en retroperitoneum.
** Regionale lymfeklieren: perigastric nodes along the lesser and greater curvatures, the nodes
along the left gastric, common hepatic, splenic and coeliac arteries, and the hepatoduodenal
nodes.
Regionale lymfeklieren van de gastro-oesophagale junctie: paracardial, left gastric, coeliac,
diaphragmatic and the lower mediastinal paraoesophageal.
*** pN0: standaard dienen in het resectie specimen minimum 16 klieren onderzocht te worden.
Indien er minder werden onderzocht, doch ze zijn allemaal negatief, wordt toch pN0 gebruikt.
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Stadium indeling:
Stadium 0:
Stadium IA:
Stadium IB:
Stadium IIA:
Stadium IIB:
Stadium IIIA:
Stadium IIIB:
Stadium IIIC:
Stadium IV:
2.
Tis
T1
T2
T1
T3
T2
T1
T4a
T3
T2
T1
T4a
T3
T2
T4b
T4a
T3
T4a
T4b
elke T
N0
N0
N0
N1
N0
N1
N2
N0
N1
N2
N3
N1
N2
N3
N0,N1
N2
N3
N3
N2,N3
elke N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
Staging
Anamnese, inclusief Helicobacter pylori status en familiaal.
Evaluatie nutritionele toestand
o NRS (nutritional risk score)
o BMI
Indien één van beiden afwijkend: consultatie Diëtiek of Nutritieteam, naargelang de ernst van
de anamnese.
Geriatrisch assessment bij patiënten vanaf 70 jaar of op indicatie
Oesofagogastroduodenoscopie + biopsies
In pre-operatieve setting en bij vermoeden van linitis plastica: RX slokdarm / maag / duodenum
(OMD)
Echo endoscopie is zeker belangrijk bij vermoeden van linitis plastica: uTN
CT thorax-abdomen of PET CT
Labo, inclusief CEA
Inventarisatie van comorbiditeiten en medicatie
Bepalen Karnofsky-score
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3.
Behandeling
1.1
CURATIEF OPERABELE TUMOREN
cT1-T2N0
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Primair heelkunde: gastrectomie + D2 lymfadenectomie
Proximale tumoren: totale gastrectomie
Distale tumoren: subtotale gastrectomie
cT3N0, cT1-3N+
Pre-operatieve chemotherapie - heelkunde - adjuvantie chemotherapie volgens de Magic trial
(Cunningham et al. 20061):
 3 cycli ECF, gevolgd door heelkunde, gevolgd door opnieuw 3 cycli ECF.
CHEMOTHERAPIE
DOSIS - TIJDSTIP
Epirubicine
50mg/m² - d1
Cisplatinum
600mg/m² - d1
5-Fluorouracil
200mg/m² - d1-21
Referentie: Cunningham et al. N Engl J Med 2006, 355(1):11-20
In geval van een hoog risico op lokaal recidief (bv. R1- of R2-resectie), wordt de post-operatieve
chemotherapie vervangen door een behandeling ovv. radiochemotherapie volgens Macdonald2 (ipv.
enkel adjuvant ECF).
DOSIS
CHEMOTHERAPIE
5-Fluorouracil
Cisplatinum
TIJDSTIP
1000 mg/m2
d1-4; wk 1, 5, 9, 13;
75 mg/m2
d1; wk 1, 5, 9, 13;
wk 1 en 5 worden concomitant met radiotherapie gegeven
RADIOTHERAPIE
25 x 1.8 Gy = 45 Gy
3D-conformele techniek
Referentie: Macdonald et al. N Engl J Med 2001, 345(10): 725-30
5 weken
Radiotherapeutisch is het belangrijk dat tijdens de chirurgie voldoende clips worden geplaatst.
Daarenboven is een goede preoperatieve CT-scan van de tumorale regio van groot belang.
Unforeseen T3 of N+ (cT1-2N0 tumoren, na heelkunde pT3 of N+)
Indien de patiënt geen neo-adjuvante behandeling ovv. chemotherapie (ECF) kreeg, maar na
heelkunde blijkt dat het gaat om een pT3 of pN+, vormt dit een indicatie voor het opstarten van postoperatieve radiochemotherapie (Macdonald et al. 2001).
1.2
INOPERABELE TUMOREN
cT4 & Stadium IV
Bij inoperabele maagtumoren zal steeds een HER2-bepaling worden uitgevoerd. In functie van het
resultaat van de HER2-bepaling en de symptomen van de patiënt wordt de systemische behandeling
bepaald.
1
2
Cunningham et al. N Engl J Med 2006, 355(1): 11-20
Macdonald et al. N Engl J Med 2001, 345(10): 725-30
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HER2-POSITIEF maagcarcinoom
CHEMOTHERAPIE
UZ Brussel
DOSIS - TIJDSTIP
80mg/m²- D1
800mg/m² gedurende D1-5
8mg/kg oplaaddosis, daarna 6mg/kg D1 om
de 3 weken
Cisplatinum
5-FU
Trastuzumab
Referentie: Bang YJ et al. Lancet 2010, 376:687-697
HER2-NEGATIEF maagcarcinoom
CHEMOTHERAPIE
Cisplatinum
5-FU
DOSIS - TIJDSTIP
50 mg/m² D1
2000 mg/m² over 46u om de 14 dagen
In specifieke gevallen wanneer volumeafname noodzakelijk is, kan bij patiënten met een goede
performance score Docetaxel/Cisplatinum en 5-FU overwogen worden (HER2 negatief
maagcarcinoom.
In specifieke gevallen bij HER2-NEGATIEF maagcarcinoom
CHEMOTHERAPIE
Docetaxel
Cisplatinum
5-FU
DOSIS - TIJDSTIP
40 mg/m² D1
40 mg/m² D1
2000 mg/m² D1-2
Referentie: Van Cutsem E et al. J Clin Oncol 2006; 24(31): 4991-7.
In individuele gevallen kunnen, in functie van de symptomen van de patiënt, tijdens een MOC
alternatieve palliatieve behandelingsopties worden overwogen:
- Externe radiotherapie ter hoogte van de primaire tumor of symptomatische metastatische
locaties.
- Chirurgie bij gastro-intestinale (sub)obstructie of tumorale bloeding.
4.
-
Opvolging na curatieve behandeling.
Klinisch onderzoek (nutritionele toestand!) om de drie maanden, gedurende de eerste 2 jaar en
nadien elke 6 maanden tot 5 jaar na de behandeling.
Bloedonderzoek, gerichte beeldvorming en endoscopische follow-up kunnen elke 6 maanden
overwogen worden gedurende de eerste 2 jaar en nadien jaarlijks tot 5 jaar.
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BIJLAGEN
Bijlage 1
Titel
Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.
Cunningham D1, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts
FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC Trial Participants.
N Engl J Med. 2006 Jul 6;355(1):11-20.
Abstract
BACKGROUND:
A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients
with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the
addition of a perioperative regimen of ECF to surgery improves outcomes among patients with
potentially curable gastric cancer.
METHODS:
We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric
junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or
surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative
cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg
per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square
meter per day) for 21 days. The primary end point was overall survival.
RESULTS:
ECF-related adverse effects were similar to those previously reported among patients with advanced
gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy
group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of
deaths within 30 days after surgery. The resected tumors were significantly smaller and less
advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149
patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As
compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of
overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009;
five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for
progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001).
CONCLUSIONS:
In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of
ECF decreased tumor size and stage and significantly improved progression-free and overall survival.
(Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).
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Bijlage 2
Titel
Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach
or gastroesophageal junction.
Macdonald JS1, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani
JA, Gunderson LL, Jessup JM, Martenson JA.
N Engl J Med. 2001 Sep 6;345(10):725-30.
Abstract
BACKGROUND:
Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We
investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of
patients with resectable adenocarcinoma of the stomach or gastroesophageal junction.
METHODS:
A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction
were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The
adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per
day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of
radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of
fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after
the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per
day) plus leucovorin (20 mg per square meter per day) were given one month apart.
RESULTS:
The median overall survival in the surgery-only group was 27 months, as compared with 36 months
in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval,
1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to
1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3
toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4
toxic effects occurred in 32 percent.
CONCLUSIONS:
Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of
adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative
resection.
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Bijlage 3
Titel:
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label,
randomised controlled trial.
Bang YJ1, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y,
Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators.
Lancet. 2010 Aug 28;376(9742):687-97
Abstract
BACKGROUND:
Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also
known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of
HER2-positive advanced gastric or gastro-oesophageal junction cancer.
METHODS:
ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised
controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal
junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by
immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were
randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus
cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in
combination with intravenous trastuzumab. Allocation was by block randomisation stratified by
Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease,
primary cancer site, and measurability of disease, implemented with a central interactive voice
recognition system. The primary endpoint was overall survival in all randomised patients who
received study medication at least once. This trial is registered with ClinicalTrials.gov, number
NCT01041404.
FINDINGS:
594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298;
chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290).
Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and
17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95%
CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in
those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most
common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs
chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs
165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse
events (17 [6%] vs 18 [6%]) did not differ between groups.
INTERPRETATION:
Trastuzumab in combination with chemotherapy can be considered as a new standard option for
patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer.
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FUNDING:
F Hoffmann-La Roche.
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Bijlage 4
Titel:
Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as
first-line therapy for advanced gastric cancer: a report of the V325 Study Group.
Van Cutsem E1, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M,
Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group.
J Clin Oncol. 2006 Nov 1;24(31):4991-7.
Abstract:
PURPOSE:
In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer
patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and
cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III
part.
PATIENTS AND METHODS:
Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75
mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2
(day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was timeto-progression (TTP).
RESULTS:
In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus
CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk
reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall
response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatment-related adverse events
occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were:
neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%).
Complicated neutropenia was more frequent with DCF than CF (29% v 12%).
CONCLUSION:
Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer
patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other
active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.
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