What is HIPEC?

 

Ovarian cancer most commonly follows a pattern of intraperitoneal spread, and even in the setting of bulky extra-ovarian disease, it can be thought of as being largely localized to the peritoneal compartment. This forms some of the rationale for performing extensive cytoreductive surgery (CRS) on ovarian cancer metastatic within the peritoneal cavity, and also some of the rationale for delivery of cytotoxic therapy directly to this compartment (intraperitoneal or “IP” chemotherapy). To be most effective, IP chemotherapy should be able to contact all peritoneal surfaces and be exposed to very low volume tumors (ideally no thicker than 2-mm implants).

There is a large body of evidence demonstrating the benefits of conventional IP chemotherapy in women who have received complete or “optimal” CRS to disease measuring less than 1 cm³.¹ However, IP chemotherapy is complicated by difficult administration and can be difficult for patients to tolerate. It is associated with significant toxicity, more so than what is seen from intravenous chemotherapy, and this toxicity is drawn out over the 18 (or more) weeks of therapy. It requires placement of an intraperitoneal port, and there are many problems associated with this foreign body including infection, malposition, and even erosions into underlying visceral structures. There are also concerns regarding the ability of the intraperitoneal infusions to reach all peritoneal surfaces when postoperative adhesions may have formed to pocket-off areas of the peritoneal cavity.

Hyperthermic intraperitoneal chemotherapy (HIPEC), at the time of CRS, is a strategy that has been explored to overcome some of these challenges.² HIPEC has the most history as an adjunct to the surgical management of gastrointestinal cancers (particularly appendiceal and colorectal). The technique first described by Dr. Paul H. Sugarbaker for gastrointestinal tumors remains similar to that performed in ovarian cancer.³ Patients first undergo extensive CRS until there is no macroscopic residual disease. Immediately following cytoreduction, catheters are placed into the peritoneal cavity, the main incision is temporarily closed (to prevent spillage), and an infusion of cytotoxic agents (commonly cisplatin, often with a second agent such as mitomycin C or doxorubicin) is warmed and then distilled into the peritoneal cavity until it is “moderately distended.” The patient’s body is then rolled back and forth to “wash” down the entire peritoneal cavity. All peritoneal surfaces can be touched by the agent as this procedure is happening intraoperatively prior to adhesion formation.

The “H” in HIPEC stands for hyperthermic, which is a key differentiator from traditional intraperitoneal and intravenous chemotherapy administration. Some chemotherapy agents, such as cisplatin, have a synergistic effect with hyperthermia. Some of these effects include increased oxygen free radical formation, increased cellular uptake of drug, reversal of mechanisms of drug resistance, and increases in DNA damage. The ideal range of hyperthermia is between 41° C and 44° C. At higher temperatures, infusions rates can be faster; however, higher temperatures are associated with more toxicity, particularly of the small bowel.⁴

 

Toxicity is a concern with HIPEC.⁵ Cytoreductive surgery for ovarian cancer can be associated with substantial morbidity, and exposing patients to prolonged operative time, extended periods of hyperthermia, and high doses of cytotoxic agents is a concern. When performed by high volume, experienced practitioners, approximately 12% of patients experience serious (grade 3-5) toxicity after CRS with HIPEC, with a procedure-related mortality of 1.2%. The majority of major toxicities were bone marrow suppression and nephrotoxicity (which in some cases can result in patients requiring hemodialysis in the immediate postoperative period). It is for this reason that most HIPEC protocols include a routine ICU admission postoperatively to closely monitor patients for major renal toxicity and electrolyte disturbances. These complications are associated with higher doses of administered cisplatin. Febrile neutropenia and gastrointestinal complications (such as bowel perforation, fistula, or anastomotic leak) also comprise the most common major toxicities. Patient factors to consider as higher risk for morbidity and mortality include underlying cardiac or pulmonary disease, poor performance status, extreme obesity, and preexisting renal disease.

While the history of HIPEC was focused around the treatment of GI peritoneal malignancies, in more recent years, the technique has been applied and studied in women with ovarian cancer.

The indications for use can vary from the upfront setting (at the time of primary CRS), following neoadjuvant chemotherapy (at the time of interval CRS), or in the recurrent setting (at the time of secondary CRS).² Possibly the most compelling study exploring HIPEC in ovarian cancer was published earlier this year in the New England Journal of Medicine.⁶ This study explored the use of HIPEC at the time of interval CRS following three cycles of neoadjuvant platinum and taxane intravenous chemotherapy. Two hundred and forty-five patients were randomly assigned at the time of optimal interval CRS to either CRS alone or CRS with HIPEC with cisplatin administered over 90 minutes. All patients received three additional cycles of intravenous platinum and taxane chemotherapy. Death was observed in a significantly higher proportion of patients in the non-HIPEC group (62% versus 50%). HIPEC was associated with a hazard ratio for death of 0.67 (P = .02). In this study, a similar number of severe adverse outcomes were observed in the two groups, though specific information was lacking, particularly with respect to renal toxicity.

These findings are intriguing and have energized interest in HIPEC by many gynecologic oncology providers; however, there are some concerns regarding the results. Patients in this study received not one intervention, but in fact three interventions (hyperthermia, an additional cycle of chemotherapy, and the peritoneal administration of chemotherapy). Any one of these three variables could explain the outcomes and it is difficult to know if all three (in the form of HIPEC) are necessary to see this observed benefit. Others have questioned the finding of no added toxicity when HIPEC is applied. This is inconsistent with what has been presented elsewhere. It is unclear from the data whether or not the nephrotoxicity was comparable between the two groups or more severe among those who received HIPEC.

An additional concern regarding HIPEC is the feasibility. Additional operative times (by up to 90 minutes), increased duration of hospitalization (including ICU admission), and additional equipment and specialized personnel are required for this technique. This may further hinder its uptake and routine practice. In the meantime, we continue to await further clinical trials that will better define the ovarian cancer patient population who might benefit from this technique and provide further data regarding its risk/benefit profile.
 

 

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

2. Helm CW et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98(4):283-90.

3. Glehen O et al. Hyperthermic intraperitoneal chemotherapy: nomenclature and modalities of perfusion. J Surg Oncol. 2008;98(4):242-6.

4. Kusamura S et al. Drugs, carrier solutions and temperature in hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2008;98(4):247-52.

5. Kusamura S et al. Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity. Ann Surg Oncol. 2007;14(9):2550-8.

6. van Driel WJ et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018 Jan;378(3):230-240.

 

Ovarian cancer most commonly follows a pattern of intraperitoneal spread, and even in the setting of bulky extra-ovarian disease, it can be thought of as being largely localized to the peritoneal compartment. This forms some of the rationale for performing extensive cytoreductive surgery (CRS) on ovarian cancer metastatic within the peritoneal cavity, and also some of the rationale for delivery of cytotoxic therapy directly to this compartment (intraperitoneal or “IP” chemotherapy). To be most effective, IP chemotherapy should be able to contact all peritoneal surfaces and be exposed to very low volume tumors (ideally no thicker than 2-mm implants).

There is a large body of evidence demonstrating the benefits of conventional IP chemotherapy in women who have received complete or “optimal” CRS to disease measuring less than 1 cm³.¹ However, IP chemotherapy is complicated by difficult administration and can be difficult for patients to tolerate. It is associated with significant toxicity, more so than what is seen from intravenous chemotherapy, and this toxicity is drawn out over the 18 (or more) weeks of therapy. It requires placement of an intraperitoneal port, and there are many problems associated with this foreign body including infection, malposition, and even erosions into underlying visceral structures. There are also concerns regarding the ability of the intraperitoneal infusions to reach all peritoneal surfaces when postoperative adhesions may have formed to pocket-off areas of the peritoneal cavity.

Hyperthermic intraperitoneal chemotherapy (HIPEC), at the time of CRS, is a strategy that has been explored to overcome some of these challenges.² HIPEC has the most history as an adjunct to the surgical management of gastrointestinal cancers (particularly appendiceal and colorectal). The technique first described by Dr. Paul H. Sugarbaker for gastrointestinal tumors remains similar to that performed in ovarian cancer.³ Patients first undergo extensive CRS until there is no macroscopic residual disease. Immediately following cytoreduction, catheters are placed into the peritoneal cavity, the main incision is temporarily closed (to prevent spillage), and an infusion of cytotoxic agents (commonly cisplatin, often with a second agent such as mitomycin C or doxorubicin) is warmed and then distilled into the peritoneal cavity until it is “moderately distended.” The patient’s body is then rolled back and forth to “wash” down the entire peritoneal cavity. All peritoneal surfaces can be touched by the agent as this procedure is happening intraoperatively prior to adhesion formation.

The “H” in HIPEC stands for hyperthermic, which is a key differentiator from traditional intraperitoneal and intravenous chemotherapy administration. Some chemotherapy agents, such as cisplatin, have a synergistic effect with hyperthermia. Some of these effects include increased oxygen free radical formation, increased cellular uptake of drug, reversal of mechanisms of drug resistance, and increases in DNA damage. The ideal range of hyperthermia is between 41° C and 44° C. At higher temperatures, infusions rates can be faster; however, higher temperatures are associated with more toxicity, particularly of the small bowel.⁴

 

Toxicity is a concern with HIPEC.⁵ Cytoreductive surgery for ovarian cancer can be associated with substantial morbidity, and exposing patients to prolonged operative time, extended periods of hyperthermia, and high doses of cytotoxic agents is a concern. When performed by high volume, experienced practitioners, approximately 12% of patients experience serious (grade 3-5) toxicity after CRS with HIPEC, with a procedure-related mortality of 1.2%. The majority of major toxicities were bone marrow suppression and nephrotoxicity (which in some cases can result in patients requiring hemodialysis in the immediate postoperative period). It is for this reason that most HIPEC protocols include a routine ICU admission postoperatively to closely monitor patients for major renal toxicity and electrolyte disturbances. These complications are associated with higher doses of administered cisplatin. Febrile neutropenia and gastrointestinal complications (such as bowel perforation, fistula, or anastomotic leak) also comprise the most common major toxicities. Patient factors to consider as higher risk for morbidity and mortality include underlying cardiac or pulmonary disease, poor performance status, extreme obesity, and preexisting renal disease.

While the history of HIPEC was focused around the treatment of GI peritoneal malignancies, in more recent years, the technique has been applied and studied in women with ovarian cancer.

The indications for use can vary from the upfront setting (at the time of primary CRS), following neoadjuvant chemotherapy (at the time of interval CRS), or in the recurrent setting (at the time of secondary CRS).² Possibly the most compelling study exploring HIPEC in ovarian cancer was published earlier this year in the New England Journal of Medicine.⁶ This study explored the use of HIPEC at the time of interval CRS following three cycles of neoadjuvant platinum and taxane intravenous chemotherapy. Two hundred and forty-five patients were randomly assigned at the time of optimal interval CRS to either CRS alone or CRS with HIPEC with cisplatin administered over 90 minutes. All patients received three additional cycles of intravenous platinum and taxane chemotherapy. Death was observed in a significantly higher proportion of patients in the non-HIPEC group (62% versus 50%). HIPEC was associated with a hazard ratio for death of 0.67 (P = .02). In this study, a similar number of severe adverse outcomes were observed in the two groups, though specific information was lacking, particularly with respect to renal toxicity.

These findings are intriguing and have energized interest in HIPEC by many gynecologic oncology providers; however, there are some concerns regarding the results. Patients in this study received not one intervention, but in fact three interventions (hyperthermia, an additional cycle of chemotherapy, and the peritoneal administration of chemotherapy). Any one of these three variables could explain the outcomes and it is difficult to know if all three (in the form of HIPEC) are necessary to see this observed benefit. Others have questioned the finding of no added toxicity when HIPEC is applied. This is inconsistent with what has been presented elsewhere. It is unclear from the data whether or not the nephrotoxicity was comparable between the two groups or more severe among those who received HIPEC.

An additional concern regarding HIPEC is the feasibility. Additional operative times (by up to 90 minutes), increased duration of hospitalization (including ICU admission), and additional equipment and specialized personnel are required for this technique. This may further hinder its uptake and routine practice. In the meantime, we continue to await further clinical trials that will better define the ovarian cancer patient population who might benefit from this technique and provide further data regarding its risk/benefit profile.
 

 

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

2. Helm CW et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98(4):283-90.

3. Glehen O et al. Hyperthermic intraperitoneal chemotherapy: nomenclature and modalities of perfusion. J Surg Oncol. 2008;98(4):242-6.

4. Kusamura S et al. Drugs, carrier solutions and temperature in hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2008;98(4):247-52.

5. Kusamura S et al. Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity. Ann Surg Oncol. 2007;14(9):2550-8.

6. van Driel WJ et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018 Jan;378(3):230-240.

 

Ovarian cancer most commonly follows a pattern of intraperitoneal spread, and even in the setting of bulky extra-ovarian disease, it can be thought of as being largely localized to the peritoneal compartment. This forms some of the rationale for performing extensive cytoreductive surgery (CRS) on ovarian cancer metastatic within the peritoneal cavity, and also some of the rationale for delivery of cytotoxic therapy directly to this compartment (intraperitoneal or “IP” chemotherapy). To be most effective, IP chemotherapy should be able to contact all peritoneal surfaces and be exposed to very low volume tumors (ideally no thicker than 2-mm implants).

There is a large body of evidence demonstrating the benefits of conventional IP chemotherapy in women who have received complete or “optimal” CRS to disease measuring less than 1 cm³.¹ However, IP chemotherapy is complicated by difficult administration and can be difficult for patients to tolerate. It is associated with significant toxicity, more so than what is seen from intravenous chemotherapy, and this toxicity is drawn out over the 18 (or more) weeks of therapy. It requires placement of an intraperitoneal port, and there are many problems associated with this foreign body including infection, malposition, and even erosions into underlying visceral structures. There are also concerns regarding the ability of the intraperitoneal infusions to reach all peritoneal surfaces when postoperative adhesions may have formed to pocket-off areas of the peritoneal cavity.

Hyperthermic intraperitoneal chemotherapy (HIPEC), at the time of CRS, is a strategy that has been explored to overcome some of these challenges.² HIPEC has the most history as an adjunct to the surgical management of gastrointestinal cancers (particularly appendiceal and colorectal). The technique first described by Dr. Paul H. Sugarbaker for gastrointestinal tumors remains similar to that performed in ovarian cancer.³ Patients first undergo extensive CRS until there is no macroscopic residual disease. Immediately following cytoreduction, catheters are placed into the peritoneal cavity, the main incision is temporarily closed (to prevent spillage), and an infusion of cytotoxic agents (commonly cisplatin, often with a second agent such as mitomycin C or doxorubicin) is warmed and then distilled into the peritoneal cavity until it is “moderately distended.” The patient’s body is then rolled back and forth to “wash” down the entire peritoneal cavity. All peritoneal surfaces can be touched by the agent as this procedure is happening intraoperatively prior to adhesion formation.

The “H” in HIPEC stands for hyperthermic, which is a key differentiator from traditional intraperitoneal and intravenous chemotherapy administration. Some chemotherapy agents, such as cisplatin, have a synergistic effect with hyperthermia. Some of these effects include increased oxygen free radical formation, increased cellular uptake of drug, reversal of mechanisms of drug resistance, and increases in DNA damage. The ideal range of hyperthermia is between 41° C and 44° C. At higher temperatures, infusions rates can be faster; however, higher temperatures are associated with more toxicity, particularly of the small bowel.⁴

 

Toxicity is a concern with HIPEC.⁵ Cytoreductive surgery for ovarian cancer can be associated with substantial morbidity, and exposing patients to prolonged operative time, extended periods of hyperthermia, and high doses of cytotoxic agents is a concern. When performed by high volume, experienced practitioners, approximately 12% of patients experience serious (grade 3-5) toxicity after CRS with HIPEC, with a procedure-related mortality of 1.2%. The majority of major toxicities were bone marrow suppression and nephrotoxicity (which in some cases can result in patients requiring hemodialysis in the immediate postoperative period). It is for this reason that most HIPEC protocols include a routine ICU admission postoperatively to closely monitor patients for major renal toxicity and electrolyte disturbances. These complications are associated with higher doses of administered cisplatin. Febrile neutropenia and gastrointestinal complications (such as bowel perforation, fistula, or anastomotic leak) also comprise the most common major toxicities. Patient factors to consider as higher risk for morbidity and mortality include underlying cardiac or pulmonary disease, poor performance status, extreme obesity, and preexisting renal disease.

While the history of HIPEC was focused around the treatment of GI peritoneal malignancies, in more recent years, the technique has been applied and studied in women with ovarian cancer.

The indications for use can vary from the upfront setting (at the time of primary CRS), following neoadjuvant chemotherapy (at the time of interval CRS), or in the recurrent setting (at the time of secondary CRS).² Possibly the most compelling study exploring HIPEC in ovarian cancer was published earlier this year in the New England Journal of Medicine.⁶ This study explored the use of HIPEC at the time of interval CRS following three cycles of neoadjuvant platinum and taxane intravenous chemotherapy. Two hundred and forty-five patients were randomly assigned at the time of optimal interval CRS to either CRS alone or CRS with HIPEC with cisplatin administered over 90 minutes. All patients received three additional cycles of intravenous platinum and taxane chemotherapy. Death was observed in a significantly higher proportion of patients in the non-HIPEC group (62% versus 50%). HIPEC was associated with a hazard ratio for death of 0.67 (P = .02). In this study, a similar number of severe adverse outcomes were observed in the two groups, though specific information was lacking, particularly with respect to renal toxicity.

These findings are intriguing and have energized interest in HIPEC by many gynecologic oncology providers; however, there are some concerns regarding the results. Patients in this study received not one intervention, but in fact three interventions (hyperthermia, an additional cycle of chemotherapy, and the peritoneal administration of chemotherapy). Any one of these three variables could explain the outcomes and it is difficult to know if all three (in the form of HIPEC) are necessary to see this observed benefit. Others have questioned the finding of no added toxicity when HIPEC is applied. This is inconsistent with what has been presented elsewhere. It is unclear from the data whether or not the nephrotoxicity was comparable between the two groups or more severe among those who received HIPEC.

An additional concern regarding HIPEC is the feasibility. Additional operative times (by up to 90 minutes), increased duration of hospitalization (including ICU admission), and additional equipment and specialized personnel are required for this technique. This may further hinder its uptake and routine practice. In the meantime, we continue to await further clinical trials that will better define the ovarian cancer patient population who might benefit from this technique and provide further data regarding its risk/benefit profile.
 

 

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

2. Helm CW et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98(4):283-90.

3. Glehen O et al. Hyperthermic intraperitoneal chemotherapy: nomenclature and modalities of perfusion. J Surg Oncol. 2008;98(4):242-6.

4. Kusamura S et al. Drugs, carrier solutions and temperature in hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2008;98(4):247-52.

5. Kusamura S et al. Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity. Ann Surg Oncol. 2007;14(9):2550-8.

6. van Driel WJ et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018 Jan;378(3):230-240.