An interview with Olivier Glehen

Professor Olivier Glehen (Centre Hospitalier Lyon-Sud, France) discussed cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) at this year’s meeting in Milan. We talked to Professor Glehen about the advantages of this treatment, current investigations and technical suggestions for surgeons performing this procedure…

Cytoreductive surgery with HIPEC is an innovative procedure used to treat cancers that have originated in or spread to the abdominal cavity, such as appendiceal cancer, pseudomyxoma peritonei, colon cancer, gastric cancer, ovarian cancer, and peritoneal mesothelioma. The procedure has several advantages compared the tradition/standard treatments, including a loco-regional treatment for a loco-regional disease, and according Professor Glehen, is the only treatment that has demonstrated that peritoneal carcinomatosis (PC) can be cured combining the treatment of macroscopic disease by CRS and the microscopic disease by HIPEC, with an approximate rate of cure of 16% among selected patients for colorectal carcinomatosis [1].

Moreover, there is also empirical evidence to supporting their use including one randomised study [2], two case control studies [3, 4] and a large international, retrospective, comparative study [5] that demonstrated the superiority of CRS and HIPEC in terms of survival vs. standard treatments (systemic chemotherapy alone).

“The role of HIPEC into this combined strategy remains unclear, as the principal prognostic factor is the residual tumour disease evaluated by the completeness cytoreduction score, this depends on CRS which represents the most important part of the combined treatment,” he explained. “Randomised studies and especially PRODIGE 7, the French study will provide some answers in the near future.”

Although he said that the mortality and morbidity rates following this kind of procedure could be considered high, they are similar to other extensive surgical procedures in digestive oncologic fields (such as for the oesophagus and pancreas). In addition, the recent intermediate results of PRODIGE 7 that compared CRS alone and CRS combined with HIPEC in colorectal carcinomatosis, showed no significant increase in postoperative complications and mortality by adding HIPEC.

Professor Glehen cautioned that the treatment is not without its risks, principally from cytoreductive surgery depending on the magnitude of surgery and according to medical literature, range from 20 to 60% for morbidity and 2 to 6% for mortality, and 10 to 15% for digestive fistula, haemorrhages, pulmonary and thromboembolic complications [9, 10] With regards to HIPEC, specific complications can occur such as renal insufficiency with the use of cisplatinum [11], haemorrhage with the use of oxaliplatin [12] and aplasia with the use of mitomycin C13.

For the surgeon, he added that there is a learning curve depending on the etiology of peritoneal disease that takes into account selection procedures, surgical skills and the management of postoperative complications [6, 7].

“Another drawback is that HIPEC in not reimbursed in most countries and combined with long surgical procedures and lengthy post-operative hospital stay, the cost of these combined procedures represent a major inconvenience to institutions that would like to develop it, [8]” he explained. “However, in most countries with centres treating peritoneal surface malignancies, the number of centres is increasing. In France, we have moved from 2-3 centres in 1995 to 25-30 in 2016, and depending on the national health regulations of each country, I believe exponential increases in the number of centres has been seen in many other countries such as the US, India, Italy, Spain and Belgium.

With regards to post-operative complications associated with the procedure, he said that specific complications related to HIPEC could be prevented by adequate and increased perioperative hydration for renal insufficiency and medical bone marrow stimulation for aplasia. He emphasised that the use of oxaliplatin should be avoided for patients at risk of postoperative haemorrhage (after extensive CRS, or for patients needed curative anticoagulation).

Professor Glehen also highlighted several absolute contra-indications to CRS and HIPEC [14] including poor general status (Performance status 2 or 3), incapability of complete or sub-complete CRS and non resectable extraperitoneal disease, and some relative contra-indications such as obesity, extensive Peritoneal Cancer Index (PCI) more than 24 (except from some rare peritoneal disease like pseudomyxome peritonei and peritoneal mesothelioma) [15], progression under systemic chemotherapy and the presence of resectable extraperitoneal disease.

“I would like to add that there are more recent results from prospective and retrospective studies from single or multi-institutional centres that have reported median survival of more than 60 months with an appropriate selection of patients. [16, 17] Consensus statements, national and international recommendations in favour of CRS and HIPEC in selected patients into specialised institutions were established and confirmed in the last International Workshop on Peritoneal Surface Malignancies in Amsterdam in 2014 [18-20],” he explained. “Furthermore, gastric cancer can be cured with a stricter patient selection [21] criteria and two meta-analysis have shown the potential benefit of CRS and intraperitoneal chemotherapy over systemic chemotherapy [22, 23].”

In addition, there are several ongoing studies that could provide some valuable insights into the treatment including the survival results from the French randomised PRODIGE 7 study that included 276 patients and compared CRS alone and CRS with HIPEC using oxaliplatin in colorectal carcinomatosis, the results are expected in two years. There is also a second French randomised study, which evaluated second look and HIPEC vs follow-up in patients at risk of peritoneal recurrence, and the study recently finished and the results are also expected in two years. Finally, the COLOPEC Dutch study is currently evaluating the proactive management of prophylactic HIPEC in patients at risk (perforated and T4 colorectal tumours).

"Because of the learning curve and specific management, there is a strong recommendation for following specialised educational program on CRS and HIPEC and to be a partner of established specialised institutions before starting a program,” he added. “Strict selection of patients (particularly at the beginning of experience) should be applied and first procedures should be performed with patients with localised peritoneal disease."

The European Society of Surgical Oncology (ESSO) runs an educational HIPEC course each year in Hamburg, attended by physicians from 25 different countries. For those interested in attending a training course, Professor Glehen suggested the following programs, which have been established to facilitate and improve CRS and HIPEC education:

• ESSO course (Dr Rau)
• French Interdisciplinary Diploma (Pr Glehen & Pr Pocard) and;
• ESSO program (Dr Deraco & Dr Gonzales Moreno)

Bibliography

1. Goere D, Malka D, Tzanis D, 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(6):1065-71.
2. 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.
3. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009; 27(5):681-5.
4. Franko J, Ibrahim Z, Gusani NJ, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. Cancer 2010; 116(16):3756-62.
5. Esquivel J, Lowy AM, Markman M, et al. The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with Peritoneal Carcinomatosis. Ann Surg Oncol 2014.
6. Yan TD, Links M, Fransi S, et al. Learning curve for cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal surface malignancy--a journey to becoming a Nationally Funded Peritonectomy Center. Ann Surg Oncol 2007; 14(8):2270-80.
7. Kusamura S, Baratti D, Deraco M. Multidimensional analysis of the learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies. Ann Surg 2011; 255(2):348-56.
8. Bonastre J, Jan P, de Pouvourville G, et al. [Cost of an intraperitoneal chemohyperthermia (IPCH) related to cytoreductive surgery]. Ann Chir 2005; 130(9):553-61.
9. Kusamura S, Younan R, Baratti D, et al. Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion: analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique. Cancer 2006; 106(5):1144-53.
10. Halkia E, Kopanakis N, Nikolaou G, Spiliotis J. Cytoreductive surgery and HIPEC for peritoneal carcinomatosis. A review on morbidity and mortality. J BUON 2015; 20 Suppl 1:S80-7.
11. Bakrin N, Classe JM, Pomel C, et al. Hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer. J Visc Surg 2014; In Press.
12. Charrier T, Passot G, Peron J, et al. Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemotherapy with Oxaliplatin Increases the Risk of Postoperative Hemorrhagic Complications: Analysis of Predictive Factors. Ann Surg Oncol 2016.
13. Glehen O, Osinsky D, Cotte E, et al. Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures. Ann Surg Oncol 2003; 10(8):863-9.
14. Glehen O MF, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol. 2004; 5:219-28.
15. Goere D, Souadka A, Faron M, 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(9):2958-64.
16. Passot G, Vaudoyer D, Cotte E, et al. Progression following neoadjuvant systemic chemotherapy may not be a contraindication to a curative approach for colorectal carcinomatosis. Ann Surg 2012; 256(1):125-9.
17. Elias D, Faron M, Iuga BS, et al. Prognostic similarities and differences in optimally resected liver metastases and peritoneal metastases from colorectal cancers. Ann Surg 2014; 261(1):157-63.
18. Slim K, Blay JY, Brouquet A, et al. Digestive oncology: surgical practices. J Chir (Paris) 2009; 146 Suppl 2:S11-80.
19. Esquivel J, Elias D, Baratti D, et al. Consensus statement on the loco regional treatment of colorectal cancer with peritoneal dissemination. J Surg Oncol 2008; 98(4):263-7.
20. Esquivel J, Piso P, Verwaal V, et al. American Society of peritoneal surface malignancies opinion statement on defining expectations from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer. J Surg Oncol 2014.
21. Chia CS, You B, Decullier E, 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(6):1971-9.
22. Coccolini F, Cotte E, Glehen O, et al. Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of randomized trials. Eur J Surg Oncol 2013; 40(1):12-26.
23. Yan TD, Black D, Sugarbaker PH, et al. 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):2702-13.