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Study Overview
Objective. To evaluate whether the addition of hyperthermic intraperotoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.
Design. Phase 3 prospective randomized clinical trial.
Setting and participants. The trial was conducted at 8 hospitals in the Netherlands and Belgium at which medical personnel had experience in administering HIPEC in patients with peritoneal disease from colon cancer or from pseudomyxoma perotinei. Eligible patients had newly diagnosed stage III epithelial ovarian, fallopian tube, or peritoneal cancer and were referred for neoadjuvant chemotherapy because of extensive abdominal disease or incomplete cytoreductive surgery (one or more residual tumors measuring > 1 cm in diameter). Eligibility criteria also including performance status score of 0 to 2, normal blood counts, and adequate renal function.
Intervention. At the time of surgery, patients were randomly assigned in a 1:1 ratio to undergo interval cytoreductive surgery either with HIPEC (surgery-plus-HIPEC group) or without HIPEC (surgery group). HIPEC was administered at the end of the cytoreductive surgical procedure. The abdomen was filled with saline that circulated continuously with the use of a roller pump through a heat exchanger. Perfusion with cisplatin at a dose of 100 mg per square meter and at a flow rate of 1 liter per minute was then initiated. The procedure took 120 minutes in total. To prevent nephrotoxicity, sodium thiosulphate was administered at the start of perfusion as an intravenous bolus (9 g per square meter in 200 mL), followed by a continuous infusion (12 g per square meter in 1000 mL) over 6 hours. Patient received in addition 3 cycles of carboplatin and paclitaxel after surgery. During follow-up, physical examinations and measurement of CA-125 level were repeated every 3 months for 2 years and then every 6 months until 5 years after the completion of chemotherapy. Computed tomography was performed at 1, 6, 12, and 24 months after the last cycle of chemotherapy.
Main outcome measure. The primary endpoint was recurrence-free survival in the intent-to-treat population. Secondary endpoints included overall survival, the side-effect profile, and health-related quality of life.
Main results. A total of 245 women were randomized between April 2007 and April 2016. The median follow-up at the time of recurrence-free survival analysis was 4.7 years. Recurrence-free survival events occurred in 81% of the HIPEC group vs 89% of the control group; median recurrence-free survival was 14.2 months vs 10.7 months, respectively (hazard ratio [HR] 0.66, P = 0.003). The benefit of HIPEC was consistent across stratification factors and post hoc subgroups. Hazard ratios (none reaching statistical significance) were 0.63 and 0.72 for those aged ≥ 65 and < 65 years; 0.69 and 0.56 for those with high-grade serous and other histology; 0.71 and 0.47 for those with no previous surgery and previous surgery; 0.64 and 0.66 for those with 0 to 5 and 6 to 8 involved regions; and 0.69 and 0.61 for those with no laparoscopy vs laparoscopy before surgery. Death occurred in 50% of the hyperthermic intraperitoneal chemotherapy group vs 62% of the control group; median overall survival was 45.7 vs 33.9 months (HR 0.67, P = 0.02).
No significant differences between the HIPEC and control groups were observed in the incidence of adverse events of any grade. The most common adverse events of any grade in the HIPEC group were nausea (63% vs 57%), abdominal pain (60% vs 575), and fatigue (37% vs 30%). Grade ≥ 3 adverse events occurred in 27% vs 25% of patients (P = 0.76). The most common grade 3 or 4 adverse events in the HIPEC group were infection (6% vs 2%), abdominal pain (5% vs 6%), and ileus (4% vs 2%). Among the patients who underwent bowel resection, a colostomy or ileostomy was performed more commonly among patients in the surgery-plus-HIPEC group (21 of 29 patients [72%]) than among those in the surgery group (13 of 30 patients [43%]) (P = 0.04).
Conclusion. Among patients with stage III epithelial ovarian cancer, the addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects.
Commentary
Ovarian cancer is associated with the highest mortality of all gynecologic cancers in the Western world [1].The majority of the patients have advanced disease at diagnosis and the most effective treatment for advanced disease involved maximum debulking surgery followed by chemotherapy. For those patients for whom primary surgery is not feasible, primary chemotherapy is given, which is followed by interval debulking after 3 courses of chemotherapy [2].However, outcome remains dismal for patients with advanced disease. Regional (intraperitoneal) chemotherapy theoretically results in a decreased rate of systemic toxic effects and may improve outcomes by eliminating residual microscopic disease more effectively than intravenous chemotherapy [3].
Intraperitoneal chemotherapy during surgery that can be delivered under hyperthermic conditions is termed hyperthermic intraperitoneal chemotherapy. Rationale for using hyperthermic conditions when delivering intraperitoneal chemotherapy is multifactorial. Clinical hyperthermia is defined as the use of temperatures of 41oC and higher. Hyperthermia itself has a direct cytotoxic effects on cells caused by impaired DNA repair, denaturation of proteins, inductions of heat-shock proteins which may serve as receptors for natural killer-cells, induction of apoptosis, and inhibition of angiogenesis. In addition to its intrinsic cytotoxic effect, hyperthermia acts in synergy with some chemotherapeutics agents and increase peritoneal and tumour drug penetration [4].
The study by van Driel et al evaluates the impact of addition of HIPEC to interval cytoreductive surgery in patients who received neoadjuvant chemotherapy for stage III epithelial ovarian cancer. Authors found that addition of HIPEC resulted in 11.8 months improvement in overall survival compared to surgery alone without increased rate of side effects.
The outcomes of the trial by van Driel et al are encouraging, but questions remain about how to apply these results in everyday clinical practice. First, with the extensive reported experience with HIPEC in select single center or multicenter trials, it is reasonable to conclude the procedure can be successfully undertaken by well-trained surgical/gynecologic oncologists and at institutions experienced in the approach. However, clinical trials have limited external validity, and while providing evidence regarding efficacy (ie, the effect of the intervention under highly selected conditions), they generally do not provide evidence of effectiveness (ie, the benefit to the general population of patients with the disease). Can the same results be reproduced in hospitals across the country? Second, what part of HIPEC was responsible for benefit? Was it merely administration of chemotherapy through intraperitoneal route? Is hyperthermia necessary to see the observed benefit in this trial? The answers to these questions are not known. Third, the assessment of cost-benefit ratio warrants serious consideration as well. As authors pointed, the addition of HIPEC resulted in extension of duration of surgery by 2 hours and a perfusionist was needed. Additional standard costs are incurred due to the use of HIPEC machine, the disposable products needed to administer HIPEC, and the 1-day stay in the ICU. Increased use of diverting colostomy and ileostomy will also increase the overall cost of the treatment.
Applications for Clinical Practice
This trial is an important step in establishing the efficacy of adding HIPEC to interval cytoreductive surgery without increasing the side effects. However, whether the same results can be reproduced at centers at which surgeons do not have as much expertise in administering HIPEC remains to be seen. New confirmatory clinical trials of HIPEC are needed before it can be recommended as a common treatment strategy.
—Deval Rajyaguru, MD, Gundersen Health System, La Crosse, WI
1. Levi F, Lucchini F, Negri E, La Vecchia C. Trends in mortality from major cancers in the European Union, including acceding countries, in 2004. Cancer 2006;101:2843–50.
2. van der Burg MEL, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629–34.
3. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43.
4. Ohno S, Siddik ZH, Kido Y, et al. Thermal enhancement of drug uptake and DNA adducts as a possible mechanism for the effect of sequencing hyperthermia on cisplatin-induced cytotoxicity in L1210 cells. Cancer Chemother Pharmacol 1994;34:302–6.
Study Overview
Objective. To evaluate whether the addition of hyperthermic intraperotoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.
Design. Phase 3 prospective randomized clinical trial.
Setting and participants. The trial was conducted at 8 hospitals in the Netherlands and Belgium at which medical personnel had experience in administering HIPEC in patients with peritoneal disease from colon cancer or from pseudomyxoma perotinei. Eligible patients had newly diagnosed stage III epithelial ovarian, fallopian tube, or peritoneal cancer and were referred for neoadjuvant chemotherapy because of extensive abdominal disease or incomplete cytoreductive surgery (one or more residual tumors measuring > 1 cm in diameter). Eligibility criteria also including performance status score of 0 to 2, normal blood counts, and adequate renal function.
Intervention. At the time of surgery, patients were randomly assigned in a 1:1 ratio to undergo interval cytoreductive surgery either with HIPEC (surgery-plus-HIPEC group) or without HIPEC (surgery group). HIPEC was administered at the end of the cytoreductive surgical procedure. The abdomen was filled with saline that circulated continuously with the use of a roller pump through a heat exchanger. Perfusion with cisplatin at a dose of 100 mg per square meter and at a flow rate of 1 liter per minute was then initiated. The procedure took 120 minutes in total. To prevent nephrotoxicity, sodium thiosulphate was administered at the start of perfusion as an intravenous bolus (9 g per square meter in 200 mL), followed by a continuous infusion (12 g per square meter in 1000 mL) over 6 hours. Patient received in addition 3 cycles of carboplatin and paclitaxel after surgery. During follow-up, physical examinations and measurement of CA-125 level were repeated every 3 months for 2 years and then every 6 months until 5 years after the completion of chemotherapy. Computed tomography was performed at 1, 6, 12, and 24 months after the last cycle of chemotherapy.
Main outcome measure. The primary endpoint was recurrence-free survival in the intent-to-treat population. Secondary endpoints included overall survival, the side-effect profile, and health-related quality of life.
Main results. A total of 245 women were randomized between April 2007 and April 2016. The median follow-up at the time of recurrence-free survival analysis was 4.7 years. Recurrence-free survival events occurred in 81% of the HIPEC group vs 89% of the control group; median recurrence-free survival was 14.2 months vs 10.7 months, respectively (hazard ratio [HR] 0.66, P = 0.003). The benefit of HIPEC was consistent across stratification factors and post hoc subgroups. Hazard ratios (none reaching statistical significance) were 0.63 and 0.72 for those aged ≥ 65 and < 65 years; 0.69 and 0.56 for those with high-grade serous and other histology; 0.71 and 0.47 for those with no previous surgery and previous surgery; 0.64 and 0.66 for those with 0 to 5 and 6 to 8 involved regions; and 0.69 and 0.61 for those with no laparoscopy vs laparoscopy before surgery. Death occurred in 50% of the hyperthermic intraperitoneal chemotherapy group vs 62% of the control group; median overall survival was 45.7 vs 33.9 months (HR 0.67, P = 0.02).
No significant differences between the HIPEC and control groups were observed in the incidence of adverse events of any grade. The most common adverse events of any grade in the HIPEC group were nausea (63% vs 57%), abdominal pain (60% vs 575), and fatigue (37% vs 30%). Grade ≥ 3 adverse events occurred in 27% vs 25% of patients (P = 0.76). The most common grade 3 or 4 adverse events in the HIPEC group were infection (6% vs 2%), abdominal pain (5% vs 6%), and ileus (4% vs 2%). Among the patients who underwent bowel resection, a colostomy or ileostomy was performed more commonly among patients in the surgery-plus-HIPEC group (21 of 29 patients [72%]) than among those in the surgery group (13 of 30 patients [43%]) (P = 0.04).
Conclusion. Among patients with stage III epithelial ovarian cancer, the addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects.
Commentary
Ovarian cancer is associated with the highest mortality of all gynecologic cancers in the Western world [1].The majority of the patients have advanced disease at diagnosis and the most effective treatment for advanced disease involved maximum debulking surgery followed by chemotherapy. For those patients for whom primary surgery is not feasible, primary chemotherapy is given, which is followed by interval debulking after 3 courses of chemotherapy [2].However, outcome remains dismal for patients with advanced disease. Regional (intraperitoneal) chemotherapy theoretically results in a decreased rate of systemic toxic effects and may improve outcomes by eliminating residual microscopic disease more effectively than intravenous chemotherapy [3].
Intraperitoneal chemotherapy during surgery that can be delivered under hyperthermic conditions is termed hyperthermic intraperitoneal chemotherapy. Rationale for using hyperthermic conditions when delivering intraperitoneal chemotherapy is multifactorial. Clinical hyperthermia is defined as the use of temperatures of 41oC and higher. Hyperthermia itself has a direct cytotoxic effects on cells caused by impaired DNA repair, denaturation of proteins, inductions of heat-shock proteins which may serve as receptors for natural killer-cells, induction of apoptosis, and inhibition of angiogenesis. In addition to its intrinsic cytotoxic effect, hyperthermia acts in synergy with some chemotherapeutics agents and increase peritoneal and tumour drug penetration [4].
The study by van Driel et al evaluates the impact of addition of HIPEC to interval cytoreductive surgery in patients who received neoadjuvant chemotherapy for stage III epithelial ovarian cancer. Authors found that addition of HIPEC resulted in 11.8 months improvement in overall survival compared to surgery alone without increased rate of side effects.
The outcomes of the trial by van Driel et al are encouraging, but questions remain about how to apply these results in everyday clinical practice. First, with the extensive reported experience with HIPEC in select single center or multicenter trials, it is reasonable to conclude the procedure can be successfully undertaken by well-trained surgical/gynecologic oncologists and at institutions experienced in the approach. However, clinical trials have limited external validity, and while providing evidence regarding efficacy (ie, the effect of the intervention under highly selected conditions), they generally do not provide evidence of effectiveness (ie, the benefit to the general population of patients with the disease). Can the same results be reproduced in hospitals across the country? Second, what part of HIPEC was responsible for benefit? Was it merely administration of chemotherapy through intraperitoneal route? Is hyperthermia necessary to see the observed benefit in this trial? The answers to these questions are not known. Third, the assessment of cost-benefit ratio warrants serious consideration as well. As authors pointed, the addition of HIPEC resulted in extension of duration of surgery by 2 hours and a perfusionist was needed. Additional standard costs are incurred due to the use of HIPEC machine, the disposable products needed to administer HIPEC, and the 1-day stay in the ICU. Increased use of diverting colostomy and ileostomy will also increase the overall cost of the treatment.
Applications for Clinical Practice
This trial is an important step in establishing the efficacy of adding HIPEC to interval cytoreductive surgery without increasing the side effects. However, whether the same results can be reproduced at centers at which surgeons do not have as much expertise in administering HIPEC remains to be seen. New confirmatory clinical trials of HIPEC are needed before it can be recommended as a common treatment strategy.
—Deval Rajyaguru, MD, Gundersen Health System, La Crosse, WI
Study Overview
Objective. To evaluate whether the addition of hyperthermic intraperotoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.
Design. Phase 3 prospective randomized clinical trial.
Setting and participants. The trial was conducted at 8 hospitals in the Netherlands and Belgium at which medical personnel had experience in administering HIPEC in patients with peritoneal disease from colon cancer or from pseudomyxoma perotinei. Eligible patients had newly diagnosed stage III epithelial ovarian, fallopian tube, or peritoneal cancer and were referred for neoadjuvant chemotherapy because of extensive abdominal disease or incomplete cytoreductive surgery (one or more residual tumors measuring > 1 cm in diameter). Eligibility criteria also including performance status score of 0 to 2, normal blood counts, and adequate renal function.
Intervention. At the time of surgery, patients were randomly assigned in a 1:1 ratio to undergo interval cytoreductive surgery either with HIPEC (surgery-plus-HIPEC group) or without HIPEC (surgery group). HIPEC was administered at the end of the cytoreductive surgical procedure. The abdomen was filled with saline that circulated continuously with the use of a roller pump through a heat exchanger. Perfusion with cisplatin at a dose of 100 mg per square meter and at a flow rate of 1 liter per minute was then initiated. The procedure took 120 minutes in total. To prevent nephrotoxicity, sodium thiosulphate was administered at the start of perfusion as an intravenous bolus (9 g per square meter in 200 mL), followed by a continuous infusion (12 g per square meter in 1000 mL) over 6 hours. Patient received in addition 3 cycles of carboplatin and paclitaxel after surgery. During follow-up, physical examinations and measurement of CA-125 level were repeated every 3 months for 2 years and then every 6 months until 5 years after the completion of chemotherapy. Computed tomography was performed at 1, 6, 12, and 24 months after the last cycle of chemotherapy.
Main outcome measure. The primary endpoint was recurrence-free survival in the intent-to-treat population. Secondary endpoints included overall survival, the side-effect profile, and health-related quality of life.
Main results. A total of 245 women were randomized between April 2007 and April 2016. The median follow-up at the time of recurrence-free survival analysis was 4.7 years. Recurrence-free survival events occurred in 81% of the HIPEC group vs 89% of the control group; median recurrence-free survival was 14.2 months vs 10.7 months, respectively (hazard ratio [HR] 0.66, P = 0.003). The benefit of HIPEC was consistent across stratification factors and post hoc subgroups. Hazard ratios (none reaching statistical significance) were 0.63 and 0.72 for those aged ≥ 65 and < 65 years; 0.69 and 0.56 for those with high-grade serous and other histology; 0.71 and 0.47 for those with no previous surgery and previous surgery; 0.64 and 0.66 for those with 0 to 5 and 6 to 8 involved regions; and 0.69 and 0.61 for those with no laparoscopy vs laparoscopy before surgery. Death occurred in 50% of the hyperthermic intraperitoneal chemotherapy group vs 62% of the control group; median overall survival was 45.7 vs 33.9 months (HR 0.67, P = 0.02).
No significant differences between the HIPEC and control groups were observed in the incidence of adverse events of any grade. The most common adverse events of any grade in the HIPEC group were nausea (63% vs 57%), abdominal pain (60% vs 575), and fatigue (37% vs 30%). Grade ≥ 3 adverse events occurred in 27% vs 25% of patients (P = 0.76). The most common grade 3 or 4 adverse events in the HIPEC group were infection (6% vs 2%), abdominal pain (5% vs 6%), and ileus (4% vs 2%). Among the patients who underwent bowel resection, a colostomy or ileostomy was performed more commonly among patients in the surgery-plus-HIPEC group (21 of 29 patients [72%]) than among those in the surgery group (13 of 30 patients [43%]) (P = 0.04).
Conclusion. Among patients with stage III epithelial ovarian cancer, the addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects.
Commentary
Ovarian cancer is associated with the highest mortality of all gynecologic cancers in the Western world [1].The majority of the patients have advanced disease at diagnosis and the most effective treatment for advanced disease involved maximum debulking surgery followed by chemotherapy. For those patients for whom primary surgery is not feasible, primary chemotherapy is given, which is followed by interval debulking after 3 courses of chemotherapy [2].However, outcome remains dismal for patients with advanced disease. Regional (intraperitoneal) chemotherapy theoretically results in a decreased rate of systemic toxic effects and may improve outcomes by eliminating residual microscopic disease more effectively than intravenous chemotherapy [3].
Intraperitoneal chemotherapy during surgery that can be delivered under hyperthermic conditions is termed hyperthermic intraperitoneal chemotherapy. Rationale for using hyperthermic conditions when delivering intraperitoneal chemotherapy is multifactorial. Clinical hyperthermia is defined as the use of temperatures of 41oC and higher. Hyperthermia itself has a direct cytotoxic effects on cells caused by impaired DNA repair, denaturation of proteins, inductions of heat-shock proteins which may serve as receptors for natural killer-cells, induction of apoptosis, and inhibition of angiogenesis. In addition to its intrinsic cytotoxic effect, hyperthermia acts in synergy with some chemotherapeutics agents and increase peritoneal and tumour drug penetration [4].
The study by van Driel et al evaluates the impact of addition of HIPEC to interval cytoreductive surgery in patients who received neoadjuvant chemotherapy for stage III epithelial ovarian cancer. Authors found that addition of HIPEC resulted in 11.8 months improvement in overall survival compared to surgery alone without increased rate of side effects.
The outcomes of the trial by van Driel et al are encouraging, but questions remain about how to apply these results in everyday clinical practice. First, with the extensive reported experience with HIPEC in select single center or multicenter trials, it is reasonable to conclude the procedure can be successfully undertaken by well-trained surgical/gynecologic oncologists and at institutions experienced in the approach. However, clinical trials have limited external validity, and while providing evidence regarding efficacy (ie, the effect of the intervention under highly selected conditions), they generally do not provide evidence of effectiveness (ie, the benefit to the general population of patients with the disease). Can the same results be reproduced in hospitals across the country? Second, what part of HIPEC was responsible for benefit? Was it merely administration of chemotherapy through intraperitoneal route? Is hyperthermia necessary to see the observed benefit in this trial? The answers to these questions are not known. Third, the assessment of cost-benefit ratio warrants serious consideration as well. As authors pointed, the addition of HIPEC resulted in extension of duration of surgery by 2 hours and a perfusionist was needed. Additional standard costs are incurred due to the use of HIPEC machine, the disposable products needed to administer HIPEC, and the 1-day stay in the ICU. Increased use of diverting colostomy and ileostomy will also increase the overall cost of the treatment.
Applications for Clinical Practice
This trial is an important step in establishing the efficacy of adding HIPEC to interval cytoreductive surgery without increasing the side effects. However, whether the same results can be reproduced at centers at which surgeons do not have as much expertise in administering HIPEC remains to be seen. New confirmatory clinical trials of HIPEC are needed before it can be recommended as a common treatment strategy.
—Deval Rajyaguru, MD, Gundersen Health System, La Crosse, WI
1. Levi F, Lucchini F, Negri E, La Vecchia C. Trends in mortality from major cancers in the European Union, including acceding countries, in 2004. Cancer 2006;101:2843–50.
2. van der Burg MEL, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629–34.
3. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43.
4. Ohno S, Siddik ZH, Kido Y, et al. Thermal enhancement of drug uptake and DNA adducts as a possible mechanism for the effect of sequencing hyperthermia on cisplatin-induced cytotoxicity in L1210 cells. Cancer Chemother Pharmacol 1994;34:302–6.
1. Levi F, Lucchini F, Negri E, La Vecchia C. Trends in mortality from major cancers in the European Union, including acceding countries, in 2004. Cancer 2006;101:2843–50.
2. van der Burg MEL, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629–34.
3. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43.
4. Ohno S, Siddik ZH, Kido Y, et al. Thermal enhancement of drug uptake and DNA adducts as a possible mechanism for the effect of sequencing hyperthermia on cisplatin-induced cytotoxicity in L1210 cells. Cancer Chemother Pharmacol 1994;34:302–6.