What is HIPEC? How does it work?

HIPEC (Hyperthermic Intra-Peritoneal Chemotherapy) is a form of mechanical, chemical, and physical regional cancer treatment that combines heat and chemotherapy, performed immediately after surgically removing the cancer from  the intra-abdominal organs and peritoneum surface. HIPEC is very different from conventional ip chemotherapy in which chemotherapy drugs are delivered into the abdominal cavity in non-operative conditions and without  heat integration. It has a direct cytotoxic effect by disrupting the DNA structure of tumor cells in hyperthermia, low pH and hypoxic conditions. Hyperthermia also has an indirect tumoricidal effect by triggering programmed cell death (apoptosis), strengthening the immune response against the tumor, increasing the penetration of drugs into the tumor tissue, and making the tumor cell more sensitive to the chemotherapy drug. As a result, heat and chemotherapy agent act synergistically in destroying cancer cells in the HIPEC process. 

 

Which tumor is HIPEC applied to?

It is applied in cancers that originate from the peritoneum itself (primary) or that have spread to the peritoneum from other organs (peritoneal metastasis). Common types of primary peritoneal cancers are peritoneal serous carcinoma and malignant peritoneal mesothelioma (MPM). Whereas ovarian (ovarian) cancer, colorectal cancer, stomach cancer and appendix tumor frequently metastasize to the peritoneum in which HIPEC is widely used as  the treatment of choice. There is an absolute indication for HIPEC, especially in tumors with mucinous histology where the effects of systemic treatments are weak and have the tendency to form pseudomyxoma peritonei (PMP). Apart from this, there is the potential to use HIPEC in all kinds of tumors that have spread (metastasized) to the peritoneum, including pancreatic and liver tumors.

 

What are the advantages and superiority of administering chemotherapy drugs via "HIPEC" over systemic treatments?

In addition to the direct and indirect thermal cytotoxic effect obtained by the extra heat, there are many other superior benefits of administering drugs this way. The most important advantages and superiorities are providing long-term contact of high local drug concentration with the tumor cell, delivering drugs to deep/hidden spots  with continuous flow, supplying  homogeneous drug distribution to the peritoneal surfaces, almost no side effects or toxicity due to minimal transfer to the systemic circulation.

Moreover, it is also possible to instantly eliminate not only free tumor cells that are exposed and  spilled to the peritoneal surface during surgery  but  can also eliminate (reverse) drug resistance.

 

To whom (under what conditions) does HIPEC apply?

HIPEC is a procedure performed following extensive tumor surgery called cytoreductive/debulking surgery (SRC). Thus, patient's medical/surgical condition should be suitable  to handle  the HIPEC in addition to  the surgery. For this reason, patient's age, systemic diseases, organ functions, nutritional status, previous treatments, ECOG performance status and the extent of the disease must be evaluated. Moreover, there is a need for a patient and motivated surgeon who is experienced in cytoreductive surgery and HIPEC applications and has the competence to manage the problems that may arise during or after these procedures, and there is also a necessity for a hospital where the patient can be cared for in the best way possible. Furthermore, there should be neither evidence nor signs of extra-abdominal disease. Finally, the post-surgical abdominal disease burden should be reduced to 'microscopic' or 'minimal residual disease' (diameter of the largest residue ≤2.5 mm).   

 

Is HIPEC effective even when chemotherapy resistance develops?

Although HIPEC is more effective in patients who have not developed chemotherapy resistance, the occurrence of such a problem does not prevent HIPEC application. Furthermore, HIPEC often reverses chemotherapy resistance of the  targeted tumor cells.

 

How is HIPEC applied, what is its technique?

Following the completion of HIPEC tumor removing/reducing surgical (SRC) procedures, catheters are inserted into the abdominal cavity and the abdomen is filled with the appropriate fluid type and amount (2-4 lt) in which various chemotherapy drugs are added. This fluid has to circulate in the abdominal cavity for certain period of time after being  heated with the help of special devices approved by the international health authorities. During the procedure, the patient's intra-abdominal and general body temperature is monitored with special probes. If necessary, the patient's extra-abdominal body regions are cooled by the anesthesia team to prevent  the risk of systemic hyperthermia. The anesthesiologist also provides the necessary fluid, blood product and drug support for the maintenance of organ and system functions. Although we were able to perform this procedure under epidural anesthesia in two of our patients due to special circumstances, the standard procedure is performed under general anesthesia. There are basically two techniques, closed (done by closing the abdomen) the most commonly used technique and open technique (done without closing the abdomen). If a connection (anastomosis) is considered in the form of a "gastro-intestinal" or "intestinal-intestinal", it is mostly done after the HIPEC procedure. While some surgeons reopen the closed abdomen and perform intra-abdominal supervision and cleaning (washing) even in cases where such a connection would not be implemented, we prefer not to open the abdomen again when a connection is not required. 

What is the implementation period in HIPEC?

Though no consensus on the ideal application time, there are procedures in  scientific literatures that range  between 30 minutes to 120 minutes. In accordance with our experience, complications increase in applications of 90 minutes or more, therefore we exercise  60 minutes of practice.

 

What should be the ideal temperature level in HIPEC?

As with the application time, there is no consensus on what the ideal temperature level should be. Standard applications can vary between 39-43 C. We make abdominal entry applications with a temperature of 42C.

 

Which chemotherapy drugs are used in HIPEC?

Although the drug to be chosen varies according to the tumor type, the most commonly used drugs are cisplatin (CDDP), oxaliplatin, mitomycin C, doxorubicin, carboplatin, paclitaxel, docetaxel, liposomal doxorubicin, melphalan, gemcitabine, 5FU and irinotecan.

 

Does HIPEC timing matter? When should it be applied?

The ideal timing for HIPEC is controversial. There are those who argue that it would be more appropriate to apply frontline (as initial treatment), interval (in surgery performed after 3-4 chemotherapy), consolidated (during the second-look surgery to be performed after the initial treatment is completed), or in relapse. In our multicenter study conducted under the umbrella of the "American Society of Peritoneal Surface Cancers", we concluded that the timing of HIPEC did not make a difference on survival. (Reference:The American Society of Peritoneal Surface Malignancies Multi-Institution Evaluation of 1,051 Advanced Ovarian Cancer Patients Undergoing Cytoreductive Surgery and HIPEC.. Foster JM, Sleightholm R, Smith L, Ceelen W, Deraco M, Yildirim Y, Levine E, Muñoz-Casares C, Glehen O, Patel A, Esquivel J. Journal of Surgical Oncology 2016; 114: 779-784)

 

What is the length of stay in intensive care and hospital after HIPEC?

Depending on the type and scope of cytoreductive surgery to be performed before HIPEC and the general condition of the patient, the length of stay varies between 3 days to 2 weeks. In our practice, 90% of our patients are discharged before one week. Our rate of admission to the intensive care unit is around 25%, and our patients who are taken to the intensive care unit can usually be transferred to the normal service room the next day.

 

Is HIPEC safe? What risks does it carry?

HIPEC has a 15% major complication (fistula, abscess, gastrointestinal leakage, bleeding, intestinal obstruction, wound dehiscence, etc.) and a 1-5% mortality risk. These rates are approximately 10 times higher than those seen in surgeries without HIPEC. Systemic complications due to surgery, drugs or heat (kidney damage, liver damage, bone marrow suppression, infection, lung problems, hemodynamic instability, excessive fluid overload, metabolic disorders, heat-stroke syndrome, neuropathy, central nervous system damage, etc.) can also be seen. Patients who have; poor general condition (ECOG performance >2), received intensive chemotherapy in the past, Peritoneal Cancer Index (PCI) >20, intestinal or urinary tract obstruction, performed multiple anastomosis, more than 4 surgical procedures (Level 3 cytoreduction) , procedure time duration >9 hours and given high doses of Cisplatin (CDDP) or Mitomycin during the procedure have an increased risk of complication and  death. Out of the 110 patients to whom we had performed HIPEC we have lost 2 of them due to procedure related complications.

 

Who administers the HIPEC treatment?

HIPEC should ideally be administered by a Surgical Oncologist (or a Gynecological Oncologist if the tumor is of gynecological origin). The specialist is also the one who performs the comprehensive and complex tumor surgery that should be done just before HIPEC. Apart from this, HIPEC can also be applied by General Surgeons who have experience in this field, although they might not have Surgical Oncology expertise.

 

What should we expect from HIPEC? How far does it contribute to life expectancy?

Although it varies depending on many factors like tumor type, disease extent, general health status of the patient, and the level of optimality of surgery, HIPEC may provide an additional survival advantage of 12 months (compared to the absence of HIPEC) in selected cases. This contribution may be higher in mesothelioma, pseudomyxoma peritoneii and some ovarian cancer patients. On the other hand, be aware of the discourses of some industry or medical professionals trying to promote HIPEC as a miracle cure are neither rational  nor supported by current scientific data. Apart from prolonging life expectancy, HIPEC can also be applied for palliative purposes such as reducing the accumulation of acid in the abdomen, reducing the risk of intestinal obstruction and prolonging “disease-free” lifespan.

 

What are the factors affecting the success of HIPEC?

Choosing the (correct) patient with the appropriate criteria is the most important factor affecting the success of HIPEC and enables to reach the goal. If the patient's condition (ECOG performance status) is good, the peritoneal cancer index (PCI) before surgery is not very high, the tumor load is minimal or invisible at the end of surgery (ie, before HIPEC), no lymph node involvement and well differentiated tumor makes  easily achievable  target  results. The surgeons’ experience  and care conditions at the  hospital are other important factors affecting the treatment success.

 

How does HIPEC affect quality of life?

In the beginningquality of life decreases slightly due to general fatigue, abdominal discomfort, and digestive complaints, which are frequently encountered in the first 6-week period after HIPEC procedure. But in the long run the quality of life increases because of decreased risks of abdominal fluid accumulation and intestinal obstruction along with  prolonged disease-free lifespan.   

 

Does HIPEC eliminate the need for systemic therapy?

HIPEC is not an alternative method to systemic treatment and the application of this procedure does not eliminate the need for systemic treatment. Following this application, patients usually receive chemotherapy and/or targeted therapy (smart drug) ranging from 3-6 cycles. Based on the results of the molecular profile analysis (biomarker/genetic testing) of the tumor, immunotherapy may also be considered in some cases.

 

Are repetitive HIPEC applications possible?

Yes it is possible. Studies have shown that repeated SRC/HIPEC is a safe approach with encouraging survival outcomes in individuals with low-volume isolated peritoneal recurrence and who have had a disease-free period of at least one year after prior HIPEC administration. Mortality and morbidity rates are similar to the initial SRC/HIPEC procedure.  

 

How is HIPEC different from PIPAC?

Although PIPAC is a form of regional chemotherapy performed through minimally invasive surgery (laparoscopy), it is quite different from HIPEC (including laparoscopic HIPEC). In this innovative method, “high pressure spray chemotherapy” is given to the peritoneal cavity for 30 minutes which is usually done in the form of 3 applications at 6-weeks interval. Compared to HIPEC, PIPAC seems to be more tolerable with less side effects. Which is mostly used for symptom palliation or improving quality of life in cases where radical surgery is not planned or possible. In this regard PIPAC can be an alternative to “Laparoscopic HIPEC”.  

 

Is HIPEC an expensive treatment? What is the cost?

SRC/HIPEC a multimodal regional treatment is a very difficult surgical procedure that requires special training with high level of expertise,  aside from being  an expensive laborious treatment with high morbidity rate. The total cost is the sum of all the three components which are: hospital care fee, surgical team fee and fee associated with the use of industrial equipment. According to the first publications reported from the USA in the 1990s (due to high complication rates, long hospitalizations, and intensive care need) treatment costs were around 160 thousand dollars, while the average cost in today's Europe is around 45 thousand dollars.  Contrary to this, treatment costs are much more affordable in our country.