Advertisement

Journal of Cancer Research and Clinical Oncology

, Volume 143, Issue 12, pp 2581–2593 | Cite as

Safety of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection: a randomized, multicenter, prospective, phase III IOCCRC trial (IOCCRC)

  • Rong-xin Zhang
  • Jun-zhong Lin
  • Jian Lei
  • Gong Chen
  • Li-ren Li
  • Zhen-hai Lu
  • Pei-rong Ding
  • Jiong-qiang Huang
  • Ling-heng Kong
  • Fu-long Wang
  • Cong Li
  • Wu Jiang
  • Chuan-feng Ke
  • Wen-hao Zhou
  • Wen-hua Fan
  • Qing Liu
  • De-sen WanEmail author
  • Xiao-jun WuEmail author
  • Zhi-zhong PanEmail author
Original Article – Clinical Oncology

Abstract

Purpose

The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone.

Methods

From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative chemotherapy, which consist of portal vein chemotherapy, intraluminal chemotherapy and intraperitoneal chemotherapy, plus surgery group, whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent.

Results

Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy-associated side effects were observed. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2 vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group. Intraoperative chemotherapy did not decrease the rate of patients who received postoperative chemotherapy between the intraoperative group and control group (29.3 vs. 30.2%, P = 0.795).

Conclusions

Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy.

ClinicalTrial.gov Register Number: NCT01465451.

Keywords

Colorectal cancer Intraoperative Chemotherapy Safety Surgery 

Notes

Acknowledgements

We would like to thank Dr. Zhi-tao Xiao and Dr. Yang Zhao for collecting clinical data. Thanks are due to Prof. J.Q. Huang in the First Affiliated Hospital of Guangzhou Medical University for the management of patients. This work was supported by Sun Yat-sen University 5010 research Fund and the National Natural Science Foundation of China (NO. 81502459).

Authors’ contribution

Zhi-zhong Pan, Xiao-jun Wu, De-sen Wan, and Jian Lei conceived and supervised this study and revised the manuscript. Rong-xin Zhang, Qing Liu, and Jun-zhong Lin interpreted the data, performed statistical analyses, and drafted the manuscript. Gong Chen, Li-ren Li, Zhen-hai Lu, Pei-rong Ding, Jiong-qiang Huang, Wen-hao Zhou, Wen-hua Fan, Ling-heng Kong, Fu-long Wang, Cong Li, Wu Jiang, and Chuan-feng Ke were responsible for treating patients and performing surgery resection. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflicts of interests.

Ethics approval

This article was approved by the Sun Yat-sen University Cancer Center ethic committee.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. Andre T et al (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109–3116. doi: 10.1200/jco.2008.20.6771 CrossRefPubMedGoogle Scholar
  2. Cennamo V et al (2009) Does stent placement for advanced colon cancer increase the risk of perforation during bevacizumab-based therapy? Clin Gastroenterol Hepatol 7:1174–1176. doi: 10.1016/j.cgh.2009.07.015 CrossRefPubMedGoogle Scholar
  3. Chen W et al (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132. doi: 10.3322/caac.21338 CrossRefPubMedGoogle Scholar
  4. Cihan S et al (2011) Adjuvant modified FOLFOX-4 in patients with stage III rectum adenocarcinoma. Asian Pac J Cancer Prev 12:967–970PubMedGoogle Scholar
  5. Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213CrossRefPubMedPubMedCentralGoogle Scholar
  6. Elferink MA, de Jong KP, Klaase JM, Siemerink EJ, de Wilt JH (2015) Metachronous metastases from colorectal cancer: a population-based study in North-East Netherlands. Int J Colorectal Dis 30:205–212. doi: 10.1007/s00384-014-2085-6 CrossRefPubMedGoogle Scholar
  7. Elias D et al (2011) Results of systematic second-look surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis. Ann Surg 254:289–293. doi: 10.1097/SLA.0b013e31822638f6 CrossRefPubMedGoogle Scholar
  8. Franko J et al (2012) 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 30:263–267. doi: 10.1200/JCO.2011.37.1039 CrossRefPubMedGoogle Scholar
  9. Grossi CE, Nealon TF Jr, Rousselot LM (1972) Adjuvant chemotherapy in resectable cancer of the colon and rectum. Surg Clin N Am 52:925–933CrossRefPubMedGoogle Scholar
  10. Grossi CE, Wolff WI, Nealson TF, Pasternack B, Ginzburg L, Rousselot LM (1975) Intraluminal and intravenous 5-FU chemotherapy adjuvant to surgery for resectable colorectal cancer. A clinical cooperative multihospital project. Panminerva Med 17:246–250PubMedGoogle Scholar
  11. Group LIM-a (1997) Portal vein chemotherapy for colorectal cancer: a meta-analysis of 4000 patients in 10 studies. Liver Infusion Meta-analysis Group. J Natl Cancer Ins 89:497–505CrossRefGoogle Scholar
  12. Hayashi N, Egami H, Kai M, Kurusu Y, Takano S, Ogawa M (1999) No-touch isolation technique reduces intraoperative shedding of tumor cells into the portal vein during resection of colorectal cancer. Surgery 125:369–374CrossRefPubMedGoogle Scholar
  13. Hompes D et al (2012) The treatment of peritoneal carcinomatosis of colorectal cancer with complete cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) with oxaliplatin: a Belgian multicentre prospective phase II clinical study. Ann Surg Oncol 19:2186–2194. doi: 10.1245/s10434-012-2264-z CrossRefPubMedGoogle Scholar
  14. Isbister WH (2002) Audit of definitive colorectal surgery in patients with early and advanced colorectal cancer. ANZ J Surg 72:271–274PubMedGoogle Scholar
  15. Ishida H et al (1999) Clinical trial of prophylactic hepatic arterial chemotherapy for liver metastases in patients with Dukes’ C colorectal cancer. Gan to kagaku ryoho. Cancer Chemother 26:1690–1693Google Scholar
  16. Klaver YL, Lemmens VE, Nienhuijs SW, Luyer MD, de Hingh IH (2012) Peritoneal carcinomatosis of colorectal origin: incidence, prognosis and treatment options. W J Gastroenterol 18:5489–5494. doi: 10.3748/wjg.v18.i39.5489 CrossRefGoogle Scholar
  17. Klaver YL, Leenders BJ, Creemers GJ, Rutten HJ, Verwaal VJ, Lemmens VE, de Hingh IH (2013) Addition of biological therapies to palliative chemotherapy prolongs survival in patients with peritoneal carcinomatosis of colorectal origin. Am J Clin Oncol 36:157–161. doi: 10.1097/COC.0b013e3182438c55 CrossRefPubMedGoogle Scholar
  18. Klaver CE et al (2015) Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial. BMC Cancer 15:428. doi: 10.1186/s12885-015-1430-7 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Klaver CEL, Stam R, Sloothaak DAM, Crezee J, Bemelman WA, Punt CJA, Tanis PJ (2017) Colorectal cancer at high risk of peritoneal metastases: long term outcomes of a pilot study on adjuvant laparoscopic HIPEC and future perspectives. Oncotarget. doi: 10.18632/oncotarget.17158 PubMedPubMedCentralGoogle Scholar
  20. Kopetz S et al (2009) Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 27:3677–3683. doi: 10.1200/jco.2008.20.5278 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM (2006) Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 244:254–259. doi: 10.1097/01.sla.0000217629.94941.cf CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ota M et al (2004) Adjuvant hepatic arterial infusion chemotherapy after curative resection for Dukes C colorectal cancer: a pilot study. Hepatogastroenterology 51:124–127PubMedGoogle Scholar
  23. Panteix G et al (1993) Study of the pharmacokinetics of mitomycin C in humans during intraperitoneal chemohyperthermia with special mention of the concentration in local tissues. Oncology 50:366–370CrossRefPubMedGoogle Scholar
  24. Pelz JO et al (2010) Evaluation of best supportive care and systemic chemotherapy as treatment stratified according to the retrospective peritoneal surface disease severity score (PSDSS) for peritoneal carcinomatosis of colorectal origin. BMC Cancer 10:689. doi: 10.1186/1471-2407-10-689 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Shukla HS, Hughes LE, Davis PW, Whitehead RH, Leach KG (1977) Distribution of 5-fluorouracil to body tissues compared after intraluminal, intravenous, and intramural administration in gastrointestinal cancer. Am J Surg 133:346–350CrossRefPubMedGoogle Scholar
  26. Sloothaak DA, Mirck B, Punt CJ, Bemelman WA, van der Bilt JD, D’Hoore A, Tanis PJ (2014) Intraperitoneal chemotherapy as adjuvant treatment to prevent peritoneal carcinomatosis of colorectal cancer origin: a systematic review. Br J Cancer 111:1112–1121. doi: 10.1038/bjc.2014.369 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Solass W, Hetzel A, Nadiradze G, Sagynaliev E, Reymond MA (2012) Description of a novel approach for intraperitoneal drug delivery and the related device. Surg Endosc 26:1849–1855. doi: 10.1007/s00464-012-2148-0 CrossRefPubMedGoogle Scholar
  28. Taylor I, Machin D, Mullee M, Trotter G, Cooke T, West C (1985) A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 72:359–363CrossRefPubMedGoogle Scholar
  29. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA (2003) Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 21:3737–3743. doi: 10.1200/JCO.2003.04.187 CrossRefPubMedGoogle Scholar
  30. Wan DS, Li GC, Zhan YQ, Chen MS (1994) Long-term outcome of 5-FU based intro-operation chemotherapy for colorectal cancer patients. J Clin Surg 2:71–73Google Scholar
  31. Wang X, Hershman DL, Abrams JA, Feingold D, Grann VR, Jacobson JS, Neugut AI (2007) Predictors of survival after hepatic resection among patients with colorectal liver metastasis. Br J Cancer 97:1606–1612. doi: 10.1038/sj.bjc.6604093 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Yu DS et al (2012) Effect of portal vein chemotherapy on liver metastasis after surgical resection of colorectal cancer. Asian Pac J Cancer Prev 13:4699–4701CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Rong-xin Zhang
    • 1
    • 2
    • 3
  • Jun-zhong Lin
    • 1
    • 2
    • 3
  • Jian Lei
    • 4
  • Gong Chen
    • 1
    • 2
    • 3
  • Li-ren Li
    • 1
    • 2
    • 3
  • Zhen-hai Lu
    • 1
    • 2
    • 3
  • Pei-rong Ding
    • 1
    • 2
    • 3
  • Jiong-qiang Huang
    • 4
  • Ling-heng Kong
    • 1
    • 2
    • 3
  • Fu-long Wang
    • 1
    • 2
    • 3
  • Cong Li
    • 1
    • 2
    • 3
  • Wu Jiang
    • 1
    • 2
    • 3
  • Chuan-feng Ke
    • 4
  • Wen-hao Zhou
    • 1
    • 2
    • 3
  • Wen-hua Fan
    • 1
    • 2
    • 3
  • Qing Liu
    • 2
    • 3
  • De-sen Wan
    • 1
    • 2
    • 3
    Email author
  • Xiao-jun Wu
    • 1
    • 2
    • 3
    Email author
  • Zhi-zhong Pan
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Colorectal Surgery, Sun Yat-sen University Cancer CentreState Key Laboratory of Oncology in South ChinaGuangzhouPeople’s Republic of China
  2. 2.State Key Laboratory of Oncology in South ChinaGuangzhouPeople’s Republic of China
  3. 3.Collaborative Innovation Center of Cancer MedicineGuangzhouPeople’s Republic of China
  4. 4.Department of General SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouPeople’s Republic of China

Personalised recommendations