Behandelingsmogelijkheden bij het maagcarcinoom: HIPEC. Johanna van Sandick, NKI-AvL, Amsterdam

Transcription

1 Behandelingsmogelijkheden bij het maagcarcinoom: HIPEC Johanna van Sandick, NKI-AvL, Amsterdam

2 Gastric cancer treatment with curative intent Macdonald et al. NEJM 2001 Cunningham et al. NEJM 2006

3 CRITICS Trial R Tissue banking Preoperative chemotherapy 3x ECC q3 weeks Preoperative chemotherapy 3x ECC q3 weeks MAGIC (3xECF) Stratification by Centre Histological type Tumour localisation D1 + surgery D1 + surgery 15 Lymph nodes No splenectomy ECC, epirubicin-cisplatin, capecitabine; IMRT, intensity modulated radiotherapy. Dikken JL, et al. BMC Cancer. 2011;11:329. 3x ECC q3 weeks Chemoradiation 45 Gy/25 fx + capecitabine-cisplatin 3D-CRT/IMRT

4 A Multicenter Randomized Phase III Trial of Neo-adjuvant Chemotherapy Followed by Surgery and Chemotherapy or by Surgery and Chemoradiotherapy in Resectable Gastric Cancer No difference in 5-year survival (43% vs 41%) The Lancet Oncology 2018

5 Gastric cancer treatment with curative intent Macdonald et al. NEJM 2001 Cunningham et al. NEJM 2006 CRITICS Lancet Oncol 2018 No improvement in 5-year survival!

6 Gastric cancer & peritoneal metastases Up to 40% of gastric cancer patients develop peritoneal metastasis during the course of their disease. The abdominal cavity is the most common site of recurrence after resection in gastric cancer. At operation, either positive peritoneal cytology or peritoneal metastasis is found in 4-25% of patients previously thought to have potentially curable disease. Feingold PL et al, J Surg Oncol 2017 (review)

7 Gastric cancer & peritoneal metastases

8

9 Gastric cancer & peritoneal metastases Median survival ~ 4 months 1 Systemic chemotherapy not (very) effective N = 706 patients ( ) 2 Use of chemotherapy increased from 9% >>> 46% Median survival unchanged (4.1 >>> 4.0 months) 1 Thomassen et al, Int. J. Cancer 2014: 134; Thomassen et al, Acta. Oncol. 2014: 53;

10 Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

11 HIPEC in gastric cancer Possible indications Treatment of manifest peritoneal metastases Positive peritoneal cytology/malignant ascites Prophylactic treatment in high risk cases

12 HIPEC in gastric cancer Why do we think it may be effective? What is the evidence so far? Will it ever be standard practice?

13 HIPEC in colorectal cancer

14 HIPEC in ovarian cancer Does it work in gastric cancer?

15 Metastatic spread in gastric cancer Liver and peritoneal metastases were commonly single metastases (while lung metastases occurred frequently together with liver metastases). Patients with liver metastases seldom had peritoneal metastases. Gastric cancer typically metastasizes either within the peritoneum or hematogenically, and seldom by both routes. Riihimaki M et al, Oncotarget 2016

16 HIPEC in gastric cancer Why do we think it may be effective? What is the evidence so far? Will it ever be standard practice?

17 HIPEC in gastric cancer

18 RCTs 9 without PC 2 with PC 9 without PC 21 non- RCTs 12 with PC

19 HIPEC in gastric cancer For patients without PC, overall survival at 5 years was in favour of the HIPEC group (RR = 0.82)

20 HIPEC in gastric cancer For patients with PC, there was no difference in 3-year overall survival between the HIPEC and control group (RR = 0.99)

21 Discussion HIPEC in gastric cancer Patient selection may play a key role in demonstrating potential benefit in HIPEC use. Current studies do not address the role and timing of systemic chemotherapy. Most trials have been performed in Asia limiting the interpretation of the results for Western populations.

22 Gill et al.

23

24 Completeness of Cytoreduction (CC) Peritoneal Cancer Index (PCI)

25 Yonemura Y, et al. World J Gastrointest Oncol 2010

26 Chia, et al. Ann Surg oncol months 22 months 11 months 8 months PCI <7 versus PCI 7 CCS 0 versus CCS 1

27 Current European Studies GASTRICHIP GASTRIPEC PERISCOPE

28 Glehen et al. BMC Cancer 2014, 14:183. N = 322 GASTRICHIP

29 N = 180 GASTRIPEC Perioperative chemotherapy: EOX, in case of HER2+: Cisplatin/Capecitabine/Trastuzumab HIPEC: Mitomycin 15 mg/m 2, Cisplatin 75 mg/m 2, 40 C Rau et al, NCT

30 Dutch Peritoneal Oncology Group PERISCOPE

31 Treatment of PERItoneal dissemination in Stomach Cancer patients with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy PERISCOPE study

32 PERISCOPE I study Aim: to study the safety and feasibility of gastrectomy combined with cytoreductive surgery (CRS) and HIPEC after neoadjuvant systemic chemotherapy as primary treatment option for advanced gastric cancer with tumour positive peritoneal cytology and/or limited peritoneal carcinomatosis.

33 PERISCOPE I study ct3-t4 (any N) resectable gastric adenocarcinoma Laparoscopy/laparotomy: tumour positive peritoneal cytology and/or limited peritoneal carcinomatosis* No disease progression during systemic chemotherapy (amendment) * limited to the upper abdominal cavity (above the transverse colon) and/or at the most at one location in the lower abdominal cavity

34 Selection of chemotherapy for intraperitoneal use in gastric cancer Braam et al, Crit Rev Oncol Hematol 2015: 95;

35 Selection of chemotherapy for intraperitoneal use in gastric cancer Combination of drugs is probably more effective. A regimen consisting of a platinum-based agent and a taxane appeared the most promising combination of drugs, as it has a good systemic effect and the known pharmacokinetic data of intraperitoneal administration are favourable. Braam et al, Crit Rev Oncol Hematol 2015: 95;

36 PERISCOPE I study Oxaliplatin (fixed dose) and docetaxel (escalating doses) Dose Level Dose Oxaliplatin (mg/m 2 ) Docetaxel (mg/m 2 ) Level Level Level Level Level MTD?

37 Van der Kaaij RT, et al, JMIR Res Protoc 2017

38 PERISCOPE II study Aim: to compare the overall survival between gastric cancer patients with limited peritoneal carcinomatosis (PCI < 7) and/or tumour positive peritoneal cytology treated with gastrectomy, cytoreductive surgery and HIPEC and those treated with the current standard treatment, i.e. systemic palliative chemotherapy.

39 Treatment of PERItoneal dissemination in Stomach Cancer patients with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy N = 106 Median survival (literature): 4 mths 75% 25% Median survival (estimated): 12 mths Median survival (estimated): 3 mths

40 INCLUSION CRITERIA Age 18 years Biopsy proven primary adenocarcinoma (or undifferentiated carcinoma) of the stomach. Including tumours at the oesophagogastric junction provided that the bulk of the tumour is located in the stomach, and, the intended surgical treatment is a gastric resection and not an oesophagectomy. A high intra-thoracic anastomosis is allowed, but not if a thoracotomy is necessary. ct3-ct4 tumour (TNM classification, 7th edition), considered to be resectable (including lymph nodes). Limited peritoneal carcinomatosis (PCI <7) and/or tumour positive peritoneal cytology confirmed by laparoscopy or laparotomy and proven by pathological examination. Treatment with systemic chemotherapy, with the latest course ending within 8 weeks prior to inclusion. All currently standard chemotherapy regimens are acceptable. Absence of disease progression during systemic chemotherapy (prior to inclusion). WHO performance status 0-2. Adequate bone marrow, hepatic and renal function. [...] For female patients who are not sterilized or in menopause... Written informed consent (after response assessment).

41 EXCLUSION CRITERIA Distant metastases (e.g., liver, lung, para-aortic lymph nodes; i.e., stations 14 and 16) Small bowel dissemination Recurrent gastric cancer Prior resection of the primary gastric tumour Non-synchronous peritoneal carcinomatosis Current other malignancy (other than cervix carcinoma and basalioma) Uncontrolled infectious disease or known infection with Human Immunodeficiency Virus A known history of hepatitis B or C with active viral replication Recent myocardial infarction (< 6 months) or unstable angina Any medical condition not yet specified above that is considered to interfere with study procedures, including adequate follow-up and compliance and/or would jeopardize safe treatment Known hypersensitivity for any of the applied chemotherapeutic agents and/or their solvents

42

43 HIPEC in gastric cancer Why do we think it may be effective? What is the evidence so far? Will it ever be standard practice?

44 HIPEC in gastric cancer YES, it has future Provided that... The concept of complete cytoreduction (CC-0) is acknowledged. Postoperative complications rates after CRS and HIPEC are within limits. Molecular profiling studies further improve patient selection.

45 Gastric cancer treatment - milestones 1997 ECF superior to FAMTX 2001 SWOG: adjuvant CRT improves overall survival 2002 REAL 2: oxaliplatin and capecitabine equally effective as CPPD and continuous 5FU (2 x 2 design) 2006 MAGIC: perioperative chemotherapy improves survival 2010 Trastuzumab improves survival of Her2+ gastric cancer..

46 Gastric cancer treatment - challenges Differentiated treatment approach according to histological subtype and molecular characteristics Optimal preoperative treatment regimen with chemotherapy and / or CRT Role of intraperitoneal chemotherapy in gastric cancer with or at risk for peritoneal carcinomatosis

47 Gastric cancer Histological subtypes Intestinal type Diffuse type

48 Gastric cancer Histological subtypes Intestinal type Diffuse type

49 Intestinal versus diffuse type gastric cancer AVL ( ) 3-year overall survival Intestinal : 73% Diffuse : 37% Stiekema et al., EJSO 2013

50 Patient compliance in postoperative phase Studie [referentie] Behandelarm Behandeling afgerond (%) SWOG [4] S CRT 64% MAGIC [5] CT S CT 42% MAGIC-B [7] ARTIST [8] CT S CT CT+B S CT+B S CT S CRT 40% 37% 75% 82% CLASSIC [9] S CT 67% TOPGEAR [10] CT S CT CT CRT S CT 60% 46% CRITICS [6] CT S CT CT S CRT 47% 52%

51 CRITICS II study

52 Neoadjuvant capecitabine, oxaliplatin, docetaxel and atezolizumab in nonmetastatic, resectable gastric and GE-junction cancer The PANDA study

53 PERISCOPE II studie Biedt de combinatiebehandeling bestaande uit een maagresectie, cytoreductieve chirurgie en HIPEC bij het peritoneaal gemetastaseerde maagcarcinoom een overlevingswinst t.o.v. de huidige standaard, nl. palliatieve systemische chemotherapie? Multicenter gerandomiseerde fase III studie (N = 106) Inclusie criteria: resectabel maagcarcinoom, beperkte peritonitis carcinomatosa (PCI < 7) en/of tumorpositieve cytologie, geen ziekte progressie tijdens systemische (voor)behandeling. Dutch Peritoneal Oncology Group Met ingang van 1 oktober 2017 voorwaardelijk toegelaten tot het basispakket van de Zorgverzekeringswet voor de duur van 5 jaar.

54