Skip to main content

Advertisement

SpringerLink
Log in

Cellular Immunoprofile of Peritoneal Environment During a HIPEC Procedure

  • Peritoneal Surface Malignancy
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

We characterized the peritoneal immune cellular profile during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in this pilot study.

Methods

We prospectively performed flow cytometric analysis of peritoneal fluid collected at laparotomy and during HIPEC at 0, 30, 60, and 90 min. Analysis consisted of standard flow cytometric leukocyte gating and the use of antibodies for stem cells, B lymphocytes, T-helper, T-suppressor, and natural killer (NK) cells.

Results

The mean peritoneal carcinomatosis index (PCI) score was 19.8 ± 11.5 (median 19). Twelve patients had a completeness of cytoreduction (CCR) score of 0–1, and three patients had a CCR score of ≥ 2 (20%). The proportion of peritoneal NK cells remained stable (p = 0.655) throughout perfusion. The CD4/CD8 ratio (p = 0.019) and granulocyte/lymphocyte ratio (p = 0.018) evolved during cytoreduction, with no further change during HIPEC. Two distinct temporal patterns of peritoneal T lymphocytes became evident (the ‘high’ and ‘low’ CD4/CD8 ratio groups) and patients maintained their high versus low peritoneal CD4/CD8 ratio status throughout the duration of HIPEC. High CD4/CD8 was associated with longer cytoreduction (p = 0.019) and borderline higher PCI score (p = 0.058). No association was identified with age (p = 0.131), sex (p = 1.000), CCR status (p = 0.580), occurrence of complication (p = 0.282), or ascites volume (p = 0.713).

Conclusion

The cellular immunoprofile of peritoneal fluid during HIPEC is stable but changes during cytoreduction. Two distinct immune groups emerged, based on CD4/CD8 ratios in the peritoneal perfusate. Further studies are warranted to evaluate peritoneal immunity and the clinical significance of novel peritoneal immune phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kuijpers AM, Mirck B, Aalbers AG, et al. Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol. Ann Surg Oncol. 2013;20(13):4224–30.

    Article  Google Scholar 

  2. Verwaal VJ, Bruin S, Boot H, van Slooten G, van Tinteren H. 8-Year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol. 2008;15(9):2426–32.

    Article  Google Scholar 

  3. Klaver CEL, Wisselink DD, Punt CJA, et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol. 2019;4(10):761–70.

    Article  Google Scholar 

  4. van den Tol MP, ten Raa S, van Grevenstein WM, van Rossen ME, Jeekel J, van Eijck CH. The post-surgical inflammatory response provokes enhanced tumour recurrence: a crucial role for neutrophils. Dig Surg. 2007;24(5):388–94.

    Article  Google Scholar 

  5. Gitzelmann CA, Mendoza-Sagaon M, Talamini MA, Ahmad SA, Pegoli W, Jr., Paidas CN. Cell-mediated immune response is better preserved by laparoscopy than laparotomy. Surgery. 2000;127(1):65–71.

    Article  CAS  Google Scholar 

  6. Kanamaru R, Ohzawa H, Miyato H, et al. Low density neutrophils (LDN) in postoperative abdominal cavity assist the peritoneal recurrence through the production of neutrophil extracellular traps (NETs). Sci Rep. 2018;8(1):632.

    Article  Google Scholar 

  7. van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018;378(3):230–40.

    Article  Google Scholar 

  8. Yang XJ, Huang CQ, Suo T, et al. 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):1575–81.

    Article  Google Scholar 

  9. Rudloff U, Langan RC, Mullinax JE, et al. Impact of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric origin: results of the GYMSSA trial. J Surg Oncol. 2014;110(3):275–84.

    Article  Google Scholar 

  10. Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol. 2010;28(1):63–8.

    Article  Google Scholar 

  11. Franko J, Ibrahim Z, Gusani NJ, Holtzman MP, Bartlett DL, Zeh HJ, 3rd. Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. Cancer. 2010;116(16):3756–62.

    Article  Google Scholar 

  12. Sugarbaker PH, Jablonski KA. Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg. 1995;221(2):124–32.

    Article  CAS  Google Scholar 

  13. Verwaal VJ, van Ruth S, de Bree E, et al. 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. 2003;21(20):3737–43.

    Article  Google Scholar 

  14. Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. J Clin Oncol. 2018;36(18 Suppl):LBA3503.

  15. Ryan D. Cytoreductive surgery and hyperthermic intraperitonal chemotherapy: history repeating itself or a new standard? ASCO 2011 Educational Book; 2011, pp. 127–128.

  16. Birnleitner H, Sachet M, Bachleitner-Hofmann T, Oehler R. Immunogenic effects of FOLFOXIRI plus Bevacizumab therapy in colorectal peritoneal carcinomatosis. In: Paper presented at the 6th immunotherapy of cancer conference (ITOC6) 11–13 April 2019; Vienna.

  17. Auer K, Bachmayr-Heyda A, Sukhbaatar N, et al. Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer. Oncotarget. 2016;7(38):61336–54.

    Article  Google Scholar 

  18. Kitayama J, Emoto S, Yamaguchi H, et al. Flow Cytometric Quantification of Intraperitoneal Free Tumor Cells is a Useful Biomarker in Gastric Cancer Patients with Peritoneal Metastasis. Ann Surg Oncol. 2015;22(7):2336–42.

    Article  Google Scholar 

  19. Cashin PH, Ghanipour L, Enblad M, Morris DL. Neutropenia in colorectal cancer treated with oxaliplatin-based hyperthermic intraperitoneal chemotherapy: an observational cohort study. World J Gastrointest Oncol. 2020;12(5):549–58.

    Article  Google Scholar 

  20. Lambert LA, Armstrong TS, Lee JJ, et al. Incidence, risk factors, and impact of severe neutropenia after hyperthermic intraperitoneal mitomycin C. Ann Surg Oncol. 2009;16(8):2181–7.

    Article  Google Scholar 

  21. Angka L, Martel AB, Kilgour M, et al. Natural killer cell IFNgamma secretion is profoundly suppressed following colorectal cancer surgery. Ann Surg Oncol. 2018;25(12):3747–54.

    Article  Google Scholar 

  22. Bellone G, Novarino A, Vizio B, et al. Impact of surgery and chemotherapy on cellular immunity in pancreatic carcinoma patients in view of an integration of standard cancer treatment with immunotherapy. Int J Oncol. 2009;34(6):1701–15.

    Article  CAS  Google Scholar 

  23. Flaherty DC, Lavotshkin S, Jalas JR, et al. Prognostic utility of immunoprofiling in colon cancer: results from a prospective, multicenter nodal ultrastaging trial. J Am Coll Surg. 2016;223(1):134–40.

    Article  Google Scholar 

  24. Jia Y, Xu L, Lin Q, et al. Levels of lymphocyte subsets in peripheral blood prior treatment are associated with aggressive breast cancer phenotypes or subtypes. Med Oncol. 2014;31(6):981.

    Article  Google Scholar 

  25. Philip MA, Standen G, Fletcher J. The effects of surgical trauma on human granulopoiesis. Br J Haematol. 1980;44(2):263–8.

    Article  CAS  Google Scholar 

  26. Saito Y, Shimada M, Utsunomiya T, et al. Regulatory T cells in the blood: a new marker of surgical stress. Surg Today. 2013;43(6):608–12.

    Article  CAS  Google Scholar 

  27. 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(2):205–13.

    Article  Google Scholar 

  28. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res. 1996;82:359–74.

    Article  CAS  Google Scholar 

  29. Lange KN, McKay D, Gentry BG, Franko J. Antimicrobial properties of perfusate fluid after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CS-HIPEC) with mitomycin C. Ann Surg Oncol. 2017;24(13):3837–41.

    Article  Google Scholar 

  30. Carey JL, McCoy JP, Keren DF. Flow cytometry in clinical diagnosis. 4th ed: ASCP; 2007.

  31. Franko J, Shi Q, Goldman CD, 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(3):263–7.

    Article  Google Scholar 

  32. Franko J, Shi Q, Meyers JP, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the analysis and research in cancers of the digestive system (ARCAD) database. Lancet Oncol. 2016;17(12):1709–19.

    Article  Google Scholar 

  33. Goldberg RM, Sargent DJ, Morton RF, et al. Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J Clin Oncol. 2006;24(21):3347–53.

    Article  CAS  Google Scholar 

  34. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  Google Scholar 

  35. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol. 2005;23(36):9441–2.

    Article  Google Scholar 

  36. Whelan RL, Franklin M, Holubar SD, et al. Postoperative cell mediated immune response is better preserved after laparoscopic vs open colorectal resection in humans. Surg Endosc. 2003;17(6):972–8.

    Article  CAS  Google Scholar 

  37. Raymond SL, Hawkins RB, Wang Z, et al. Prospective validation of a transcriptomic metric in severe trauma. Ann Surg. 2020;271(5):802–10.

    Article  Google Scholar 

  38. Torres K, Torres A, Chroscicki A, et al. Evaluation of lymphocytes CD4 + and CD8 + and expression of ZAP-70 kinase on CD3 + and CD19 + lymphocytes in obese patients undergoing laparoscopic cholecystectomy. Surg Endosc. 2013;27(3):872–9.

    Article  Google Scholar 

  39. Sugarbaker PH. Peritoneal surface oncology: review of a personal experience with colorectal and appendiceal malignancy. Tech Coloproctol. 2005;9(2):95–103.

    Article  CAS  Google Scholar 

  40. Glehen O, Kwiatkowski F, Sugarbaker PH, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. J Clin Oncol. 2004;22(16):3284–92.

    Article  CAS  Google Scholar 

  41. Levine EA, Blazer DG 3rd, Kim MK, et al. Gene expression profiling of peritoneal metastases from appendiceal and colon cancer demonstrates unique biologic signatures and predicts patient outcomes. J Am Coll Surg. 2012;214(4):599–606; discussion 606–597.

  42. Verwaal VJ, van Tinteren H, van Ruth S, Zoetmulder FA. Predicting the survival of patients with peritoneal carcinomatosis of colorectal origin treated by aggressive cytoreduction and hyperthermic intraperitoneal chemotherapy. Br J Surg. 2004;91(6):739–46.

    Article  CAS  Google Scholar 

  43. Levine EA, Stewart JHt, Russell GB, Geisinger KR, Loggie BL, Shen P. Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures. J Am Coll Surg. 2007;204(5):943–53; discussion 953–45.

  44. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.

    Article  CAS  Google Scholar 

  45. Jones JC, Renfro LA, Al-Shamsi HO, et al. (Non-V600) BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 2017;35(23):2624–30.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Surgical Oncology, MercyOne Medical Center, Des Moines, IA, USA

    Jan Franko MD, PhD, Rushin Brahmbhatt MD, May Tee MD, MPH, Shankar Raman MD, Benjamin Ferrel DO, Marc Gorvet DO & Matthew Andres DO

  2. Department of Pathology, MercyOne Medical Center, Des Moines, IA, USA

    Matthew Andres DO

Authors
  1. Jan Franko MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rushin Brahmbhatt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. May Tee MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shankar Raman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benjamin Ferrel DO
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marc Gorvet DO
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthew Andres DO
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan Franko MD, PhD.

Ethics declarations

Disclosure

Jan Franko, Rushin Brahmbhatt, May Tee, Shankar Raman, Benjamin Ferrel, Marc Gorvet, and Matthew Andres declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Franko, J., Brahmbhatt, R., Tee, M. et al. Cellular Immunoprofile of Peritoneal Environment During a HIPEC Procedure. Ann Surg Oncol 27, 5005–5013 (2020). https://doi.org/10.1245/s10434-020-08870-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-020-08870-3

Search

Navigation