Several methods of delivering hyperthermic intraperitoneal chemotherapy (HIPEC) during the course of cytoreductive surgery have been described, but no significant differences in treatment results have been found among them. HIPEC is a safe treatment for the patient and for healthcare workers involved in the procedure provided standard protective and environmental measures are used. This article describes the different techniques in use and the technology available for the administration of HIPEC. Also reviewed are the safety features that must be taken into consideration when performing this procedure. Recommended guidelines to prevent associated occupational hazards are provided.
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Several methods of delivering HIPEC have been described but no significant differences in treatment outcomes, morbidity, or safety have been found among them. The ultimate choice is left to individual preference or institutional criteria.
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Administration of HIPEC is safe for operating room personnel; chemotherapy exposure during the procedure is negligible provided universal precautions, individual protection measures, and environmental safety guidelines are followed.
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Proper education of operating room staff about the essentials of HIPEC and on the proper handling of chemotherapy is the first safety requirement.
Introduction
Selected patients with peritoneal surface malignancies benefit from a radical therapeutic approach consisting of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy (PIC), which may be complemented by systemic chemotherapy. Numerous studies have shown the efficacy of this strategy, which has led to survival results unknown to date, even in the era of last-generation chemotherapy and biologic agents. Its clinical application is fully developed and well-established in specialized centers.
The ultimate purpose of PIC is to kill in situ microscopic cancer cells or minute tumor nodules left behind after the performance of (complete) cytoreductive surgery. The specific contribution of PIC to the oncologic outcomes observed for the combined procedure remains to be elucidated, and is currently being addressed by the ongoing French randomized trial PRODIGE-7.
PIC may be administered with hyperthermic intraperitoneal chemotherapy (HIPEC) during the course of cytoreductive surgery, in the first 4 or 5 days after surgery in normothermic conditions (EPIC), or as a combination of both. Randomized controlled studies have not been performed to formally assess which modality of PIC is more advantageous. A few retrospective comparative studies are available showing a trend for or even an advantage for HIPEC alone over HIPEC followed by EPIC or EPIC alone, in terms of morbidity (fistula formation), although not in terms of survival, but these conclusions need to be interpreted with caution. A recent small retrospective case-control Swedish study reports a survival advantage of HIPEC over sequential postoperative intraperitoneal chemotherapy after complete cytoreduction in colorectal carcinomatosis. It can be stated without a doubt that HIPEC is nowadays the primary method of PIC used by every surgical team treating peritoneal surface diseases and that EPIC (combined with HIPEC or on its own) has a more limited penetration among them.
The acronym HIPEC, coined by the group from the Netherlands Cancer Institute, became the standardized nomenclature for this procedure as a result of the experts’ consensus achieved during the Fourth International Workshop on Peritoneal Surface Malignancy (Madrid, 2004). HIPEC combines the pharmacokinetic advantage inherent to the intracavitary delivery of certain cytotoxic drugs, which results in regional dose intensification, with the direct cytotoxic effect of hyperthermia. Hyperthermia exhibits a selective cell-killing effect in malignant cells by itself, potentiates the cytotoxic effect of certain chemotherapy agents, and enhances the tissue penetration of the administered drug.
This article describes the different techniques in use and the technology available for the administration of HIPEC. Also reviewed are the safety features that must be taken into consideration when performing this procedure. Recommended guidelines to prevent associated occupational hazards are provided.
HIPEC methods
Description
HIPEC is delivered in the operating room (OR) after the cytoreductive surgical procedure is finalized if a complete cytoreduction has been achieved (CC-0/CC-1). There are two main methods for intraperitoneal administration of hyperthermic chemotherapy: open abdomen technique and closed abdomen technique. Over the years mixed methods (semiopen or semiclosed) have been reported.
The open method is usually performed by the “coliseum technique,” as described by Sugarbaker ( Fig. 1 ). After the cytoreductive phase has been finalized, four closed suction drains are placed through the abdominal wall and made watertight with a 3/0 monofilament purse-string suture at the skin. These drains remain in place for the postoperative period. An inflow line is placed over the abdominal wall into the peritoneal cavity and may be secured by a silk tie at the retractor frame. A different number of temperature probes may be used for intraperitoneal temperature monitoring; at least one in the in-flow line or under the right diaphragm and another one at a distance from this point (pelvis) are used, but a more intensive monitoring may be used. Probe tips may be secured with a silk tie to the tip of the corresponding drains to prevent migration. The skin edges of the abdominal incision are suspended up to a self-retaining retractor whose frame has previously been elevated 15 to 20 cm over the patient, thus creating an open space in the abdominal cavity. This is done by a running monofilament number 1 suture. A plastic sheet is incorporated into this suture to prevent chemotherapy solution splashing from occurring. A slit in the plastic cover is made to allow the surgeon’s double gloved hand access to the abdomen and pelvis. Impervious gown and protection goggles are mandatory. A smoke evacuator is placed under the plastic sheet to clear chemotherapy vapors or small droplets that may be liberated during the procedure. During the 30 to 90 minutes of perfusion, all the anatomic structures within the peritoneal cavity and the laparotomy incision are uniformly exposed to heat and chemotherapy by continuous manual stirring of the perfusate performed by the surgeon.
A variation of the open technique described and mainly used in Japan uses a device called “peritoneal cavity expander” (PCE). The PCE is an acrylic cylinder containing inflow and outflow lines that is secured over the laparotomy wound. When filled with heated perfusate, the PCE can accommodate the small bowel, allowing it to float freely and be manipulated within the perfusate. After HIPEC is completed, the perfusate is drained, and the PCE is removed. Fujimura and colleagues and Yonemura and colleagues reported about HIPEC with a PCE in carcinomatosis from various malignancies. The use of the PCE is very limited (if any) at the present time and has rarely been used outside Japan. Its interest in this paper is somewhat historical.
In the closed method catheters and temperature probes are placed as described previously, but the laparotomy skin edges are sutured watertight, so that perfusion is done in a closed circuit ( Fig. 2 ). The abdominal wall is externally agitated during the perfusion period to promote uniform perfusate and heat distribution, because pooling of these possibly leading to subsequent morbidity is a reasonable concern in this method. A larger volume of perfusate is generally needed to establish the circuit compared with the open technique, and also a higher abdominal pressure is achieved during the perfusion, which may facilitate drug tissue penetration. After perfusion, the abdomen is reopened and the perfusate is evacuated. Appropriate anastomoses are performed and the abdomen is closed in the standard fashion. Other teams perform anastomoses and proceed with a definitive closure of the abdomen before HIPEC is started.
The mixed methods (semiopen or semiclosed) have been developed at a later time as an evolution of an open method, to further reduce the chance of OR staff exposure to chemotherapy and prevent heat loss. Rat and colleagues use a latex sheet (abdominal cavity expander) water-tight sutured to the skin edges and then secured to the retractor frame, allowing a controlled overflow of the perfusate and allowing its level to reach well above the skin edges with no spillage. A transparent methacrylate cover with a laparoscopy hand port in its center is placed over the retractor’s frame and the latex piece hermetically closing the abdominal cavity. Sugarbaker also reported the use of a closed acrylic device with a lid, mounted on top of the coliseum to provide perfusate containment while allowing manual access to the peritoneal cavity for manipulation.
Comparative Analysis and Choice of HIPEC Method
Each HIPEC method has its own advantages and disadvantages, as shown in Table 1 . It should be noted that, to the authors’ knowledge, no formal prospective controlled comparison of HIPEC methods has been performed. Elias and colleagues performed an early phase trial in which they successively tested seven HIPEC procedures. The authors concluded that closed methods were not satisfactory and that the open technique with traction of the skin upward was superior in terms of technical feasibility, thermal homogeneity, and perfusate distribution. Ortega-Deballon and colleagues recently published a comparative experimental study in a small number of pigs concluding that intraperitoneal hyperthermia can be achieved with both techniques and that the open technique had higher systemic absorption and abdominal tissue penetration of chemotherapy (oxaliplatin) than the closed technique.
| Feature | Open | Closed | Mixed (semiopen/semiclosed) |
|---|---|---|---|
| Heat and chemotherapy distribution | More uniform a | Uneven b | More uniform a |
| Heat dissipation | More b | Less a | Improved (less) compared with open a |
| Time to achieve target temperature | Longer b | Shorter a | Shorter compared with open a |
| Direct contact of surgeon with chemotherapy (with protection) | Yes b | No a | Yes b |
| Risk of chemotherapy exposure by operating room staff | Theoretically increased b | Minimized a | Minimized a |
| Risk of thermal injury | Minimized a | Possible b | Minimized a |
| Complexity in assembling | Some (more complex if using peritoneal cavity expander) a | None a | More complex (expander, metacrylate cover, hand port) b |
a Contains possible advantages.
The panel of experts assembled for the 2006 Consensus Conference in Milan, after review of scientific evidence, discussion, and voting using the Delphi methodology, concluded that there is no evidence to establish the superiority of one method over the others regarding patient outcomes, morbidity, or surgical staff safety. A call for future studies to definitively answer this question was made but has not been answered. Therefore, any of the methods listed previously may be used for the delivery of HIPEC.
The criteria that may be taken into consideration when choosing a HIPEC method by emerging treatment programs are mostly subjective: (1) the perceived risk of environmental chemotherapy exposure (the real risk is negligible if proper safety measures are followed, as described later); (2) concerns on possible differences in the uniform distribution of chemotherapy or heat throughout the peritoneal cavity that may result in visceral thermal injury; and (3) possible differences in dosaging and perfusate volume inherent to the closed method.
Each program should use the method that best fits its institutional needs or demands in terms of operational features, safety, and occupational hazard regulations, becoming used to deal with its own advantages and disadvantages. Safety standards and considerations for the administration of HIPEC are addressed in detail later in this article. Undoubtedly, as for any surgical technique, previous experience with one of them (eg, during a training period) has an impact on the choice; however, some teams have changed their method of choice over time, even after extensive experience with one technique.
HIPEC methods
Description
HIPEC is delivered in the operating room (OR) after the cytoreductive surgical procedure is finalized if a complete cytoreduction has been achieved (CC-0/CC-1). There are two main methods for intraperitoneal administration of hyperthermic chemotherapy: open abdomen technique and closed abdomen technique. Over the years mixed methods (semiopen or semiclosed) have been reported.
The open method is usually performed by the “coliseum technique,” as described by Sugarbaker ( Fig. 1 ). After the cytoreductive phase has been finalized, four closed suction drains are placed through the abdominal wall and made watertight with a 3/0 monofilament purse-string suture at the skin. These drains remain in place for the postoperative period. An inflow line is placed over the abdominal wall into the peritoneal cavity and may be secured by a silk tie at the retractor frame. A different number of temperature probes may be used for intraperitoneal temperature monitoring; at least one in the in-flow line or under the right diaphragm and another one at a distance from this point (pelvis) are used, but a more intensive monitoring may be used. Probe tips may be secured with a silk tie to the tip of the corresponding drains to prevent migration. The skin edges of the abdominal incision are suspended up to a self-retaining retractor whose frame has previously been elevated 15 to 20 cm over the patient, thus creating an open space in the abdominal cavity. This is done by a running monofilament number 1 suture. A plastic sheet is incorporated into this suture to prevent chemotherapy solution splashing from occurring. A slit in the plastic cover is made to allow the surgeon’s double gloved hand access to the abdomen and pelvis. Impervious gown and protection goggles are mandatory. A smoke evacuator is placed under the plastic sheet to clear chemotherapy vapors or small droplets that may be liberated during the procedure. During the 30 to 90 minutes of perfusion, all the anatomic structures within the peritoneal cavity and the laparotomy incision are uniformly exposed to heat and chemotherapy by continuous manual stirring of the perfusate performed by the surgeon.
A variation of the open technique described and mainly used in Japan uses a device called “peritoneal cavity expander” (PCE). The PCE is an acrylic cylinder containing inflow and outflow lines that is secured over the laparotomy wound. When filled with heated perfusate, the PCE can accommodate the small bowel, allowing it to float freely and be manipulated within the perfusate. After HIPEC is completed, the perfusate is drained, and the PCE is removed. Fujimura and colleagues and Yonemura and colleagues reported about HIPEC with a PCE in carcinomatosis from various malignancies. The use of the PCE is very limited (if any) at the present time and has rarely been used outside Japan. Its interest in this paper is somewhat historical.
In the closed method catheters and temperature probes are placed as described previously, but the laparotomy skin edges are sutured watertight, so that perfusion is done in a closed circuit ( Fig. 2 ). The abdominal wall is externally agitated during the perfusion period to promote uniform perfusate and heat distribution, because pooling of these possibly leading to subsequent morbidity is a reasonable concern in this method. A larger volume of perfusate is generally needed to establish the circuit compared with the open technique, and also a higher abdominal pressure is achieved during the perfusion, which may facilitate drug tissue penetration. After perfusion, the abdomen is reopened and the perfusate is evacuated. Appropriate anastomoses are performed and the abdomen is closed in the standard fashion. Other teams perform anastomoses and proceed with a definitive closure of the abdomen before HIPEC is started.
The mixed methods (semiopen or semiclosed) have been developed at a later time as an evolution of an open method, to further reduce the chance of OR staff exposure to chemotherapy and prevent heat loss. Rat and colleagues use a latex sheet (abdominal cavity expander) water-tight sutured to the skin edges and then secured to the retractor frame, allowing a controlled overflow of the perfusate and allowing its level to reach well above the skin edges with no spillage. A transparent methacrylate cover with a laparoscopy hand port in its center is placed over the retractor’s frame and the latex piece hermetically closing the abdominal cavity. Sugarbaker also reported the use of a closed acrylic device with a lid, mounted on top of the coliseum to provide perfusate containment while allowing manual access to the peritoneal cavity for manipulation.
Comparative Analysis and Choice of HIPEC Method
Each HIPEC method has its own advantages and disadvantages, as shown in Table 1 . It should be noted that, to the authors’ knowledge, no formal prospective controlled comparison of HIPEC methods has been performed. Elias and colleagues performed an early phase trial in which they successively tested seven HIPEC procedures. The authors concluded that closed methods were not satisfactory and that the open technique with traction of the skin upward was superior in terms of technical feasibility, thermal homogeneity, and perfusate distribution. Ortega-Deballon and colleagues recently published a comparative experimental study in a small number of pigs concluding that intraperitoneal hyperthermia can be achieved with both techniques and that the open technique had higher systemic absorption and abdominal tissue penetration of chemotherapy (oxaliplatin) than the closed technique.
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Pharmacology of Perioperative Intraperitoneal and Intravenous Chemotherapy in Patients with Peritoneal Surface Malignancy
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