Laarbeeklaan 101 1090 Brussel Oncologisch Handboek Richtlijnen Digestieve Oncologie Maag V3.15
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 = oordeel over primaire tumor niet mogelijk T0 = geen primaire tumor Tis = carcinoma in situ/hooggradige dysplasie T1 = 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 = oordeel over regionale lymfeklieren niet mogelijk N0 = geen regionale lymfekliermetastasen N1 = metastasen in 1-2 regionale lymfeklieren N2 = metastasen in 3-6 regionale lymfeklieren N3 = 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. Richtlijnen Digestieve Oncologie Maag - 2 -
Stadium indeling: Stadium 0: Tis N0 M0 Stadium IA: T1 N0 M0 Stadium IB: T2 N0 M0 T1 N1 M0 Stadium IIA: T3 N0 M0 T2 N1 M0 T1 N2 M0 Stadium IIB: T4a N0 M0 T3 N1 M0 T2 N2 M0 T1 N3 M0 Stadium IIIA: T4a N1 M0 T3 N2 M0 T2 N3 M0 Stadium IIIB: T4b N0,N1 M0 T4a N2 M0 T3 N3 M0 Stadium IIIC: T4a N3 M0 T4b N2,N3 M0 Stadium IV: elke T elke N M1 2. 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 3. Behandeling 1.1 CURATIEF OPERABELE TUMOREN ct1-t2n0 Richtlijnen Digestieve Oncologie Maag - 3 -
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. 2006 1 ): 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 Macdonald 2 (ipv. enkel adjuvant ECF). CHEMOTHERAPIE 5-Fluorouracil Cisplatinum DOSIS TIJDSTIP 1000 mg/m 2 d1-4; wk 1, 5, 9, 13; 75 mg/m 2 d1; wk 1, 5, 9, 13; wk 1 en 5 worden concomitant met radiotherapie gegeven RADIOTHERAPIE 25 x 1.8 Gy = 45 Gy 5 weken 3D-conformele techniek Referentie: Macdonald et al. N Engl J Med 2001, 345(10): 725-30 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 Cunningham et al. N Engl J Med 2006, 355(1): 11-20 2 Macdonald et al. N Engl J Med 2001, 345(10): 725-30 Richtlijnen Digestieve Oncologie Maag - 4 -
HER2-POSITIEF maagcarcinoom CHEMOTHERAPIE DOSIS - TIJDSTIP Cisplatinum 80mg/m²- D1 5-FU 800mg/m² gedurende D1-5 Trastuzumab 8mg/kg oplaaddosis, daarna 6mg/kg D1 om de 3 weken 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 DOSIS - TIJDSTIP Docetaxel Cisplatinum 5-FU 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. Richtlijnen Digestieve Oncologie Maag - 5 -
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].). Richtlijnen Digestieve Oncologie Maag - 6 -
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. Richtlijnen Digestieve Oncologie Maag - 7 -
Bijlage 3 Titel: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2- positive 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. Richtlijnen Digestieve Oncologie Maag - 8 -
FUNDING: F Hoffmann-La Roche. Richtlijnen Digestieve Oncologie Maag - 9 -
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. Richtlijnen Digestieve Oncologie Maag - 10 -