Phase I/II study of oxaliplatin dose escalation via a laparoscopic approach using pressurized aerosol intraperitoneal chemotherapy (PIPOX trial) for nonresectable peritoneal metastases of digestive cancers (stomach, small bowel and colorectal): Rationale and design

Frédéric Dumont, Hélène Senellart, Francois Pein, Loic Campion, Olivier Glehen, Diane Goere, Marc Pocard, Emilie Thibaudeau, Frédéric Dumont, Hélène Senellart, Francois Pein, Loic Campion, Olivier Glehen, Diane Goere, Marc Pocard, Emilie Thibaudeau

Abstract

Background: The annual incidence of gastrointestinal carcinomas (stomach, small bowel, colon and rectum) is increasing in Western countries, reaching 50,000 new cases each year in France. Peritoneal carcinomatosis (PC) is diagnosed in 15% of these patients. Complete cytoreductive surgery (CCS) plus Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is the only therapy that can offer patients with PC a chance for long-term survival with a 5 year overall survival (OS) rate of 30-60% versus 0-5% with systemic chemotherapy alone. However, CCS plus HIPEC still presents serious limitations and very few patients (10%) are candidates for these radical treatments. PC remains a palliative setting for 90% of patients with a median survival ranging from 15 to 25 months. Innovative surgical therapies such as Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) therefore need to be developed to improve the prognosis. Potential benefits were obtained after intraperitoneal nebulization of oxaliplatin in patients with advanced PC from colorectal cancer. Innovative surgical therapies such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been proposed as palliative locoregional treatment with some promising results. The dose of oxaliplatin currently established by nebulization (PIPAC) is really low at 92 mg/m2. However, the peritoneum acts as a barrier limiting the systemic passage of intraperitoneal drug. Oxaliplatin used at higher doses during PIPAC procedures could be a safe option and allow better intratumoral penetration of chemotherapy.

Method and design: The proposed study is a multicenter phase I/II trial of oxaliplatin dose escalation during PIPAC. The aim is to determine the maximum tolerated dose of pressurized oxaliplatin administered by the intraperitoneal route (PIPAC) during two consecutive procedures at a 4-6 week interval for patients with extended peritoneal carcinomatosis from the gastrointestinal tract. Dose started at 90 mg/m2 and escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m2.

Discussion: Oxaliplatin is an effective drug in gastrointestinal cancer and high doses given by the intraperitoneal route during HIPEC are well tolerated. In this phase I trial, we hypothesized that high-dose oxaliplatin during PIPAC is feasible and safe. The repeated local administration of high doses of oxaliplatin could improve tumor response and prognosis.

Trial registration: Prospective study. ClinicalTrials.gov: NCT03294252. EudraCT: 2016-003666-49.

Keywords: PIPAC; colorectal carcinoma; gastrointestinal carcinoma; oxaliplatin; peritoneal carcinomatosis.

Conflict of interest statement

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Figures

Figure 1:
Figure 1:
Dose escalation according to a “3+3” Fibonacci sequence.
Figure 2:
Figure 2:
Treatment schedule.

References

    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistic. CA Cancer J Clin. 2011;61:69–90.
    1. Jéhannin-Ligier K, Dantony E, Bossard N, Molinié F, Defossez G, Daubisse-Marliac L, et al. Projection de l’incidence et de la moratlité par cancer en France métropolitaine en 2017. Rapport technique. Saint-Maurice: Santé publique, 2017. 80.
    1. Quere P, Facy O, Manfredi S, Jooste V, Faivre J, Lepage C, et al. Epidemiology, management, and survival of peritoneal carcinomatosis from colorectal cancer: A population-based study. Dis Colon Rectum. 2015;58:743–52.
    1. Seyfried F, Von Rahden BH, Miras AD, Gasser M, Maeder U, Kunzmann V, et al. Incidence, time course and independent risk factors for metachronous peritoneal carcinomatosis of gastric origin–A longitudinal experience from a prospectively collected database of 1108 patients. BMC Cancer. 2015;15:73.
    1. Chia CS, You B, Decullier E, Lorimier G, Abboud K, Bereder JM, et al. Patients with peritoneal carcinomatosis from gastric cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Is cure a possibility? Ann Surg Oncol. 2016;23:1971–9.
    1. Goéré D, Malka D, Tzanis D, Gava V, Boige V, Eveno C, et al. Is there a possibility of a cure in patients with colorectal peritoneal carcinomatosis amenable to complete cytoreductive surgery and intraperitoneal chemotherapy? Ann Surg. 2013;257:1065–71.
    1. Levine EA, Stewert JH, IV, Shen P, Russell GB, Loggie BL, Votanopoulos KI. Intraperitoneal chemotherapy for peritoneal surface malignancy: Experience with 1,000 patients. J Am Coll Surg. 2014;218:573–85.
    1. Liu Y, Yonemura Y, Levine EA, Mizumoto A, Hirano M, Sako S, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal dissemination from small bowel malignancy: Results from a single specialized center. Ann Surg Oncol. 2016;23:1625–31.
    1. Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal F, Classe JM, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol. 2009;27:681–5.
    1. Franko J, Shi Q, Goldman CD, Pockaj BA, Nelson GD, Goldberg RM, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: A pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol. 2012;30:263–7.
    1. Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: Results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88:358–63.
    1. Razenberg LG, Van Gestel YR, Lemmens VE, De Hingh IH, Creemers GJ. Bevacizumab in addition to palliative chemotherapy for patients with peritoneal carcinomatosis of colorectal origin: A nationwide population-based study. Clin Colorectal Cancer. 2016;15:41–6.
    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;43:972–80.
    1. Thomassen I, Van Gestel YR, Van Ramshorst B, Luyer MD, Bosscha K, Nienhuijs SW, et al. Peritoneal carcinomatosis of gastric origin: A population-based study on incidence, survival and risk factors. Int J Cancer. 2014;134:622–8.
    1. Chua TC, Yan TD, Saxena A, Morris DL. Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: A systematic review of morbidity and mortality. Ann Surg. 2009;249:900–7.
    1. Glehen O, Gilly FN, Boutitie F, Bereder JM, Quenet F, Sideris L, et al. Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: A multi-institutional study of 1,290 patients. Cancer. 2010;116:5608–18.
    1. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res. 1996;82:359–74.
    1. Goéré D, Souadka A, Faron M, Cloutier AS, Viana B, Honoré C, et al. Extent of colorectal peritoneal carcinomatosis: Attempt to define a threshold above which HIPEC does not offer survival benefit: A comparative study. Ann Surg Oncol. 2015;22:2958–64.
    1. Coccolini F, Catena F, Glehen O, Yonemura Y, Sugarbaker PH, Piso P, et al. Complete versus incomplete cytoreduction in peritoneal carcinosis from gastric cancer, with consideration to PCI cut-off. Systematic review and meta-analysis. Eur J Surg Oncol. 2015;41:911–9.
    1. Mogal H, Chouliaras K, Levine EA, Shen P, Votanopoulos KI. Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: Review of indications and outcomes. J Gastrointest Oncol. 2016;7:129–42.
    1. Esquis P, Consolo D, Magnin G, Pointaire P, Moretto P, Ynsa MD, et al. High intra-abdominal pressure enhances the penetration and antitumor effect of intraperitoneal cisplatin on experimental peritoneal carcinomatosis. Ann Surg. 2006;244:106–12.
    1. Solaß W, Hetzel A, Nadiradze G, Sagynaliev E, Reymond MA. Description of a novel approach for intraperitoneal drug delivery and the related device. Surg Endosc. 2012;26:1849–55.
    1. Demtröder C, Solass W, Zieren J, Strumberg D, Giger-Pabst U, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin in colorectal peritoneal metastasis. Colorectal Dis. 2016;18:364–71.
    1. Nadiradze G, Giger-Pabst U, Zieren J, Strumberg D, Solass W, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with low-dose cisplatin and doxorubicin in gastric peritoneal metastasis. J Gastrointest Surg. 2016;20:367–73.
    1. Elias D, Bonnay M, Puizillou JM, Antoun S, Demirdjian S, El OA, et al. Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: Pharmacokinetics and tissue distribution. Ann Oncol. 2002;13:267–72.
    1. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–13.
    1. Common Terminology Criteria for Adverse Events v 4.0 (CTCAE)
    1. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Final results from PRIME: Randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014;25:1346–55.
    1. Xiang XJ, Liu YW, Zhang L, Qiu F, Yu F, Zhan ZY, et al. A phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma. Anticancer Drugs. 2012;23:561–6.
    1. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.
    1. Pomel C, Ferron G, Lorimier G, Rey A, Lhomme C, Classe JM, et al. Hyperthermic intra-peritoneal chemotherapy using oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma. Results of a phase II prospective multicentre trial. CHIPOVAC study. Eur J Surg Oncol. 2010;36:589–93.
    1. Maindrault-Goebel F, De Gramont A, Louvet C, André T, Carola E, Gilles V, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology multidisciplinary research group (GERCOR). Ann Oncol. 2000;11:1477–83.
    1. Alcindor T, Beauger N. Oxaliplatin: A review in the era of molecularly targeted therapy. Curr Oncol. 2011;18:18–25.

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