Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma - the phase III "PREVENT"- (FLOT9) trial of the AIO /CAOGI /ACO

Thorsten O Götze, Pompiliu Piso, Sylvie Lorenzen, Ulli S Bankstahl, Claudia Pauligk, Moustafa Elshafei, Giuseppe Amato, Daniel Reim, Wolf O Bechstein, Alfred Königsrainer, Stefan P Mönig, Beate Rau, Matthias Schwarzbach, Salah-Eddin Al-Batran, Thorsten O Götze, Pompiliu Piso, Sylvie Lorenzen, Ulli S Bankstahl, Claudia Pauligk, Moustafa Elshafei, Giuseppe Amato, Daniel Reim, Wolf O Bechstein, Alfred Königsrainer, Stefan P Mönig, Beate Rau, Matthias Schwarzbach, Salah-Eddin Al-Batran

Abstract

Background: The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40-50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60-70% of tumors of diffuse type, compared to only 20-30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since pts. with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published.

Methods: This is a multicenter, randomized, controlled, open-label study including a total of 200 pts. with localized and locally advanced diffuse or mixed type (Laurens's classification) adenocarcinoma of the stomach and Type II/III GEJ. All enrolled pts. will have received 3-6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m2; Oxaliplatin 85 mg/m2; Leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (control arm) or surgery + intraoperative HIPEC (cisplatin 75 mg/m2 solution administered at a temperature of 42 °C for 90 min) and postoperative FLOT (experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, rate of pts. with peritoneal relapse at 2 and 3 years, perioperative morbidity/mortality and quality of life. The trial starts with a safety run-in phase. After 20 pts. had curatively intended resection in Arm B, an interim safety analysis is performed. Recruitment has already started and first patient in was on January 18th, 2021.

Discussion: If the PREVENT concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, pts. with gastric cancer and no peritoneal involvement will not be treated with HIPEC during surgery.

Trial registration: The study is registered on June 25th, 2020 under ClinicalTrials.gov Identifier: NCT04447352 ; EudraCT: 2017-003832-35 .

Keywords: Cisplatin; FLOT- regimen; Gastrectomy; Gastric cancer; Gastroesophageal junction cancer; HIPEC; Hyperthermic intraperitoneal chemotherapy; Lauren- classification; Peritoneal carcinomatosis; Quality of life; Signet ring cells.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
PREVENT (FLOT9) study flow chart (schematic)

References

    1. Duarte I, Llanos O. Patterns of metastases in intestinal and diffuse types of carcinoma of the stomach. Hum Pathol. 1981;12(3):237–242. doi: 10.1016/S0046-8177(81)80124-4.
    1. Esaki Y, Hirayama R, Hirokawa K. A comparison of patterns of metastasis in gastric cancer by histologic type and age. Cancer. 1990;65(9):2086–2090. doi: 10.1002/1097-0142(19900501)65:9<2086::AID-CNCR2820650933>;2-B.
    1. Haraguchi M, Okamura T, Korenaga D, Tsujitani S, Marin P, Sugimachi K. Heterogeneity of DNA ploidy in patients with undifferentiated carcinomas of the stomach. Cancer. 1987;59(5):922–924. doi: 10.1002/1097-0142(19870301)59:5<922::AID-CNCR2820590511>;2-0.
    1. Maehara Y, Moriguchi S, Orita H, Kakeji Y, Haraguchi M, Korenaga D, Sugimachi K. Lower survival rate for patients with carcinoma of the stomach of Borrmann type IV after gastric resection. Surg Gynecol Obstet. 1992;175(1):13–16.
    1. Rhomberg W, Gruber U. Liver metastasis in cancer of the stomach and its dependence on the histology of the primary tumor: an autopsy study on 102 cases. Clin Exp Metastasis. 1989;7(6):585–590. doi: 10.1007/BF01753669.
    1. Al-Shammaa HA, Li Y, Yonemura Y. Current status and future strategies of cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. World J Gastroenterol. 2008;14(8):1159–1166. doi: 10.3748/wjg.14.1159.
    1. Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016;17(12):1697–1708. doi: 10.1016/s1470-2045(16)30531-9.
    1. Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948–1957. doi: 10.1016/s0140-6736(18)32557-1.
    1. Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26(9):1435–1442. doi: 10.1200/JCO.2007.13.9378.
    1. Al-Batran SE, Homann N, Pauligk C, Illerhaus G, Martens UM, Stoehlmacher J, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial. JAMA Oncol. 2017;3(9):1237–1244. doi: 10.1001/jamaoncol.2017.0515.
    1. Al-Batran SE, Pauligk C, Homann N, Hartmann JT, Moehler M, Probst S, et al. The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: a randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+) Eur J Cancer. 2013;49(4):835–842. doi: 10.1016/j.ejca.2012.09.025.
    1. van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HWR, Hermans RHM, de Hingh IHJT, van der Velden J, Arts HJ, Massuger LFAG, Aalbers AGJ, Verwaal VJ, Kieffer JM, van de Vijver KK, van Tinteren H, Aaronson NK, Sonke GS. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378(3):230–240. doi: 10.1056/NEJMoa1708618.
    1. Tanis PJ, Tuynman JB, de Hingh I. Results from the PROPHYLOCHIP-PRODIGE 15 trial. Lancet Oncol. 2020;21(11):e496. doi: 10.1016/s1470-2045(20)30497-6.
    1. Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):256–266. doi: 10.1016/s1470-2045(20)30599-4.
    1. Liu Y, Yonemura Y, Levine EA, Glehen O, Goere D, Elias D, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for peritoneal metastases from a small bowel adenocarcinoma: multi-institutional experience. Ann Surg Oncol. 2018;25(5):1184–1192. doi: 10.1245/s10434-018-6369-x.
    1. Schmiegel W, Buchberger B, Follmann M, Graeven U, Heinemann V, Langer T, Nothacker M, Porschen R, Rödel C, Rösch T, Schmitt W, Wesselmann S, Pox C. Not available. Z Gastroenterol. 2017;55(12):1344–1498. doi: 10.1055/s-0043-121106.
    1. S3-Leitlinie Kolorektales Karzinom . Leitlinienprogramm Onkologie S3-Leitlinie Kolorektales Karzinom August 2014. 2014.
    1. Glehen O, Gilly FN, Arvieux C, Cotte E, Boutitie F, Mansvelt B, et al. Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy. Ann Surg Oncol. 2010;17(9):2370–2377. doi: 10.1245/s10434-010-1039-7.
    1. Xu DZ, Zhan YQ, Sun XW, Cao SM, Geng QR. Meta-analysis of intraperitoneal chemotherapy for gastric cancer. World J Gastroenterol. 2004;10(18):2727–2730. doi: 10.3748/wjg.v10.i18.2727.
    1. Yu W, Whang I, Suh I, Averbach A, Chang D, Sugarbaker PH. Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer. Ann Surg. 1998;228(3):347–354. doi: 10.1097/00000658-199809000-00007.
    1. Fujimoto S, Takahashi M, Mutou T, Kobayashi K, Toyosawa T. Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma. Cancer. 1999;85(3):529–534. doi: 10.1002/(SICI)1097-0142(19990201)85:3<529::AID-CNCR3>;2-9.
    1. Yonemura Y, de Aretxabala X, Fujimura T, Fushida S, Katayama K, Bandou E, Sugiyama K, Kawamura T, Kinoshita K, Endou Y, Sasaki T. Intraoperative chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomized controlled study. Hepatogastroenterology. 2001;48(42):1776–1782.
    1. Kim JY, Bae HS. A controlled clinical study of serosa-invasive gastric carcinoma patients who underwent surgery plus intraperitoneal hyperthermo-chemo-perfusion (IHCP) Gastric Cancer. 2001;4(1):27–33. doi: 10.1007/s101200100013.
    1. Yan TD, Black D, Sugarbaker PH, Zhu J, Yonemura Y, Petrou G, Morris DL. A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Ann Surg Oncol. 2007;14(10):2702–2713. doi: 10.1245/s10434-007-9487-4.
    1. Coccolini F, Cotte E, Glehen O, Lotti M, Poiasina E, Catena F, Yonemura Y, Ansaloni L. Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of randomized trials. Eur J Surg Oncol. 2014;40(1):12–26. doi: 10.1016/j.ejso.2013.10.019.
    1. Al-Batran SE, Goetze TO, Mueller DW, Vogel A, Winkler M, Lorenzen S, et al. The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI. BMC Cancer. 2017;17(1):893. doi: 10.1186/s12885-017-3918-9.
    1. Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018;36(19):1922–1929. doi: 10.1200/jco.2018.77.8613.
    1. Jacquet P, Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res. 1996;82:53–63. doi: 10.1007/978-1-4613-1247-5_4.
    1. Yonemura Y, Canbay E, Li Y, Coccolini F, Glehen O, Sugarbaker PH, Morris D, Moran B, Gonzaletz-Moreno S, Deraco M, Piso P, Elias D, Batlett D, Ishibashi H, Mizumoto A, Verwaal V, Mahtem H. A comprehensive treatment for peritoneal metastases from gastric cancer with curative intent. Eur J Surg Oncol. 2016;42(8):1123–1131. doi: 10.1016/j.ejso.2016.03.016.
    1. Chu DZ, Lang NP, Thompson C, Osteen PK, Westbrook KC. Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer. 1989;63(2):364–367. doi: 10.1002/1097-0142(19890115)63:2<364::aid-cncr2820630228>;2-v.
    1. Oh SY, Kwon HC, Lee S, Lee DM, Yoo HS, Kim SH, Jang JS, Kim MC, Jeong JS, Kim HJ. A phase II study of oxaliplatin with low-dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFOX-4) for gastric cancer patients with malignant ascites. Jpn J Clin Oncol. 2007;37(12):930–935. doi: 10.1093/jjco/hym131.
    1. Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, Fontaumard E, Brachet A, Caillot JL, Faure JL, Porcheron J, Peix JL, François Y, Vignal J, Gilly FN. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88(2):358–363. doi: 10.1002/(sici)1097-0142(20000115)88:2<358::aid-cncr16>;2-o.
    1. Shirao K, Boku N, Yamada Y, Yamaguchi K, Doi T, Goto M, et al. Randomized phase III study of 5-fluorouracil continuous infusion vs. sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106) Jpn J Clin Oncol. 2013;43(10):972–980. doi: 10.1093/jjco/hyt114.
    1. Yamao T, Shimada Y, Shirao K, Ohtsu A, Ikeda N, Hyodo I, Saito H, Iwase H, Tsuji Y, Tamura T, Yamamoto S, Yoshida S. Phase II study of sequential methotrexate and 5-fluorouracil chemotherapy against peritoneally disseminated gastric cancer with malignant ascites: a report from the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group, JCOG 9603 trial. Jpn J Clin Oncol. 2004;34(6):316–322. doi: 10.1093/jjco/hyh063.
    1. Dedrick RL, Myers CE, Bungay PM, DeVita VT., Jr Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep. 1978;62(1):1–11.
    1. Witkamp AJ, de Bree E, Van Goethem R, Zoetmulder FA. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev. 2001;27(6):365–374. doi: 10.1053/ctrv.2001.0232.
    1. Desiderio J, Chao J, Melstrom L, Warner S, Tozzi F, Fong Y, Parisi A, Woo Y. The 30-year experience-a meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer. Eur J Cancer. 2017;79:1–14. doi: 10.1016/j.ejca.2017.03.030.
    1. Hall JJ, Loggie BW, Shen P, Beamer S, Douglas Case L, McQuellon R, Geisinger KR, Levine EA. Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for advanced gastric cancer. J Gastrointest Surg. 2004;8(4):454–463. doi: 10.1016/j.gassur.2003.12.014.
    1. Yang XJ, Huang CQ, Suo T, Mei LJ, Yang GL, Cheng FL, Zhou YF, Xiong B, Yonemura Y, Li Y. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011;18(6):1575–1581. doi: 10.1245/s10434-011-1631-5.
    1. Yarema RR, Ohorchak MA, Zubarev GP, Mylyan YP, Oliynyk YY, Zubarev MG, Gyrya PI, Kovalchuk YJ, Safiyan VI, Fetsych TG. Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: results of a single-centre retrospective study. Int J Hyperth. 2014;30(3):159–165. doi: 10.3109/02656736.2014.893451.
    1. Sun J, Song Y, Wang Z, Gao P, Chen X, Xu Y, Liang J, Xu H. Benefits of hyperthermic intraperitoneal chemotherapy for patients with serosal invasion in gastric cancer: a meta-analysis of the randomized controlled trials. BMC Cancer. 2012;12(1):526. doi: 10.1186/1471-2407-12-526.
    1. Glehen O, Passot G, Villeneuve L, Vaudoyer D, Bin-Dorel S, Boschetti G, Piaton E, Garofalo A. GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study. BMC Cancer. 2014;14(1):183. doi: 10.1186/1471-2407-14-183.
    1. Pasqual EM, Bertozzi S, Londero AP, Brandolin D, Mariuzzi L, De Pellegrin A, et al. Microscopic peritoneal carcinomatosis in gastric cancer: prevalence, prognosis and predictive factors. Oncol Lett. 2018;15(1):710–716. doi: 10.3892/ol.2017.7442.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi