Total laparoscopic hysterectomy versus abdominal hysterectomy in the treatment of patients with early stage endometrial cancer:A randomized multi center study

BACKGROUND: Traditionally standard treatment for patients with early stage endometrial cancer (EC) is total abdominal hysterectomy and bilateral salpingo oophorectomy (TAH+BSO) with or without lymph node dissection through a vertical midline incision. While TAH is an accepted effective treatment, it is highly invasive, visibly scarring and associated with morbidity. An alternative treatment is the same operation by laparoscopy. Though in several studies total laparoscopic hysterectomy (TLH+ BSO) seems a safe and feasible alternative approach in early stage endometrial cancer patients, there are no randomized data available yet. Furthermore, a randomized controlled trial with surgeons trained in laparoscopy is warranted in order to implement this technique in a safe manner. The aim of this study is to compare the treatment related morbidity, cost-effectiveness and quality of life in early stage endometrial cancer patients treated by laparoscopy versus the standard open approach.METHODS: A multi centre randomized clinical phase 3 trial, including 5 university hospitals and 15 regional hospitals in the Netherlands. Only gynecologists trained in performing a TLH are allowed to participate.INCLUSION CRITERIA: Patients with a clinical stage I endometrioid adenocarcinoma or complex atypical hyperplasia are randomized in a 2:1 allocation to receive TLH or TAH. The main outcome measure is the rate of major complications, as assessed by an independent clinical review board. In total, 275 patients are required to have 80% power at alpha-0.05 to detect a significant difference of 15% complication rate. Secondary outcome measures are 1) costs and cost-effectiveness, 2) minor complications, and 3) quality of life. All data from this multi center study are reported using case record forms. Data regarding quality of life, pain, body Image, sexuality and additional homecare are assessed with self reported questionnaires.DISCUSSION: A randomized multi center study in early stage endometrial cancer patients with inclusion criteria for patients and surgeons is designed and ongoing. Results will be presented at the end of 2009.TRIAL REGISTRATION: Dutch trial register number NTR821.</p

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

BACKGROUND: Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer. METHODS: In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points. RESULTS: In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76). CONCLUSIONS: Among patients with stage III epithelial ovarian cancer, the addition of HIPEC 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. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257 ; EudraCT number, 2006-003466-34 .)

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

The majority of patients with ovarian cancer (OC) receive an initial diagnosis of advanced disease that has spread from the ovaries to the peritoneal surface. The most effective treatment for patients with advanced disease is cytoreductive surgery followed by systemic chemotherapy. As an alternative, interval cytoreductive surgery is performed after 3 cycles of chemotherapy. Following these treatments, the primary site of disease recurrence is the peritoneal surface. Delivery of chemotherapy by the intraperitoneal (IP) route enhances drug delivery at the peritoneal surface and eliminates residual microscopic peritoneal disease more efficiently than intravenous administration. Previous trials have shown that after primary cytoreductive surgery combined use of intravenous and IP chemotherapy results in longer overall survival among patients with stage III OC compared with intravenous administration alone. Combined intravenous/IP chemotherapy has several drawbacks that have hampered its adoption in many countries. These include catheter-related problems, increased demands on the patient, and gastrointestinal and renal adverse effects. Most of these drawbacks can be circumvented by delivery of the IP chemotherapy at the end of surgery. Delivery of IP chemotherapy during surgery under hyperthermic conditions—termed hyperthermic IP chemotherapy (HIPEC)—increases the penetration of chemotherapy at the peritoneal surface. Although addition of HIPEC to interval cytoreductive surgery is feasible in women with OC, efficacy data from randomized trials are lacking. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of interval cytoreductive surgery with HIPEC as compared with interval cytoreductive surgery without HIPEC in patients with stage III epithelial OC. Subjects were patients receiving neoadjuvant chemotherapy who had at least stable disease after 3 cycles of carboplatin (area under the curve of 5–6 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area). Of these patients, 245 were randomized: 122 to the surgery-plus-HIPEC group and 123 to the surgery-without-HIPEC group. Randomization was performed at the time of surgery in cases in which surgery that would result in complete cytoreduction (no visible disease) or optimal cytoreduction (≥1 residual tumors measuring ≤10 mm in diameter) was deemed to be feasible. Patients received an additional 3 cycles of carboplatin and paclitaxel postoperatively. Recurrence-free survival was the primary study end point. Key secondary end points were overall survival and the side effect profile. Data for recurrence-free and overall survival were analyzed according to intention to treat. Among patients who underwent cytoreductive surgery, disease recurrence or death occurred in 89% (110/123) of patients in the surgery-without-HIPEC group and 81% (99/122) of patients in the surgery-plus-HIPEC group; the hazard ratio for disease recurrence or death was 0.66, with a 95% confidence interval of 0.50 to 0.87, P = 0.003. The median recurrence-free survival was 3.5 months longer in the surgery-plus-HIPEC group than in the surgery-without-HIPEC group (14.2 vs 10.7 months). At a median follow-up of 4.7 years, 62% (76/123) of patients in the surgery-without-HIPEC group and 50% (61/122) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% confidence interval, 0.48–0.94; P = 0.02). There were no significant differences in the incidence of adverse events of any grade between the 2 groups (25% in the surgery-withoutHIPEC group and 27% in the surgery-plus-HIPEC group, P = 0.76). These data indicate that among patients with stage III epithelial OC addition of HIPEC to interval cytoreductive surgery provides longer recurrence-free survival and overall survival compared with surgery alone and no higher rates of adverse effects

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

BACKGROUND: Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer. METHODS: In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points. RESULTS: In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76). CONCLUSIONS: Among patients with stage III epithelial ovarian cancer, the addition of HIPEC 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. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257 ; EudraCT number, 2006-003466-34 .)

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

The majority of patients with ovarian cancer (OC) receive an initial diagnosis of advanced disease that has spread from the ovaries to the peritoneal surface. The most effective treatment for patients with advanced disease is cytoreductive surgery followed by systemic chemotherapy. As an alternative, interval cytoreductive surgery is performed after 3 cycles of chemotherapy. Following these treatments, the primary site of disease recurrence is the peritoneal surface. Delivery of chemotherapy by the intraperitoneal (IP) route enhances drug delivery at the peritoneal surface and eliminates residual microscopic peritoneal disease more efficiently than intravenous administration. Previous trials have shown that after primary cytoreductive surgery combined use of intravenous and IP chemotherapy results in longer overall survival among patients with stage III OC compared with intravenous administration alone. Combined intravenous/IP chemotherapy has several drawbacks that have hampered its adoption in many countries. These include catheter-related problems, increased demands on the patient, and gastrointestinal and renal adverse effects. Most of these drawbacks can be circumvented by delivery of the IP chemotherapy at the end of surgery. Delivery of IP chemotherapy during surgery under hyperthermic conditions—termed hyperthermic IP chemotherapy (HIPEC)—increases the penetration of chemotherapy at the peritoneal surface. Although addition of HIPEC to interval cytoreductive surgery is feasible in women with OC, efficacy data from randomized trials are lacking. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of interval cytoreductive surgery with HIPEC as compared with interval cytoreductive surgery without HIPEC in patients with stage III epithelial OC. Subjects were patients receiving neoadjuvant chemotherapy who had at least stable disease after 3 cycles of carboplatin (area under the curve of 5–6 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area). Of these patients, 245 were randomized: 122 to the surgery-plus-HIPEC group and 123 to the surgery-without-HIPEC group. Randomization was performed at the time of surgery in cases in which surgery that would result in complete cytoreduction (no visible disease) or optimal cytoreduction (≥1 residual tumors measuring ≤10 mm in diameter) was deemed to be feasible. Patients received an additional 3 cycles of carboplatin and paclitaxel postoperatively. Recurrence-free survival was the primary study end point. Key secondary end points were overall survival and the side effect profile. Data for recurrence-free and overall survival were analyzed according to intention to treat. Among patients who underwent cytoreductive surgery, disease recurrence or death occurred in 89% (110/123) of patients in the surgery-without-HIPEC group and 81% (99/122) of patients in the surgery-plus-HIPEC group; the hazard ratio for disease recurrence or death was 0.66, with a 95% confidence interval of 0.50 to 0.87, P = 0.003. The median recurrence-free survival was 3.5 months longer in the surgery-plus-HIPEC group than in the surgery-without-HIPEC group (14.2 vs 10.7 months). At a median follow-up of 4.7 years, 62% (76/123) of patients in the surgery-without-HIPEC group and 50% (61/122) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% confidence interval, 0.48–0.94; P = 0.02). There were no significant differences in the incidence of adverse events of any grade between the 2 groups (25% in the surgery-withoutHIPEC group and 27% in the surgery-plus-HIPEC group, P = 0.76). These data indicate that among patients with stage III epithelial OC addition of HIPEC to interval cytoreductive surgery provides longer recurrence-free survival and overall survival compared with surgery alone and no higher rates of adverse effects

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1):final survival analysis of a randomised, controlled, phase 3 trial

Background: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up.Methods: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18–76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0–2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed.Findings: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4–12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5–13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6–12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0–18·5]; hazard ratio [HR] 0·63 [95% CI 0·48–0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0–39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6–55·1]; HR 0·70 [95% CI 0·53–0·92], stratified log-rank p=0·011).Interpretation: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery.Funding: Dutch Cancer Foundation (KWF Kankerbestrijding).</p

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1):final survival analysis of a randomised, controlled, phase 3 trial

Background: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up.Methods: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18–76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0–2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed.Findings: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4–12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5–13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6–12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0–18·5]; hazard ratio [HR] 0·63 [95% CI 0·48–0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0–39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6–55·1]; HR 0·70 [95% CI 0·53–0·92], stratified log-rank p=0·011).Interpretation: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery.Funding: Dutch Cancer Foundation (KWF Kankerbestrijding).</p

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1):final survival analysis of a randomised, controlled, phase 3 trial

Background: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up.Methods: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18–76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0–2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed.Findings: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4–12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5–13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6–12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0–18·5]; hazard ratio [HR] 0·63 [95% CI 0·48–0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0–39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6–55·1]; HR 0·70 [95% CI 0·53–0·92], stratified log-rank p=0·011).Interpretation: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery.Funding: Dutch Cancer Foundation (KWF Kankerbestrijding).</p