Background
Laparoscopy has acquired an increasing role in the management of ovarian cancer. Laparoscopic cytoreduction could represent a new frontier for selected patients after neoadjuvant chemotherapy (NACT).
Objective
We sought to assess feasibility and early complication rate of minimally invasive (MI) interval debulking surgery (IDS) in stage III-IV epithelial ovarian cancer (EOC) patients after NACT.
Study Design
This is a phase II multicentric study in advanced EOC cases with clinical complete response after NACT, according to Gynecologic Cancer Intergroup and Response Evaluation Criteria In Solid Tumors criteria. Institutional review board approval was obtained and all patients signed written informed consent to be included in the protocol. The study was registered in clinicaltrials.gov ( NCT02324595 ) and was named “MISSION” trial. For patients meeting inclusion criteria, surgical procedures started with diagnostic laparoscopy to confirm preoperative findings and assess surgical complexity. MI-IDS included hysterectomy, bilateral salpingo-oophorectomy, appendectomy, omentectomy, peritonectomy, and bowel resection. Pelvic and/or aortic lymphadenectomy was not considered as standard procedure in these cases. Intraoperative and postoperative outcomes, time to restart chemotherapy, survival rate, and quality of life data were registered.
Results
From December 2013 through February 2015, of 184 advanced EOC patients considered eligible for IDS, 52 (28.2%) met inclusion criteria and were enrolled in the study. For 22 (12%) of them, standard laparotomic approach was preferred because of intraoperative surgeon evaluation. Thirty (16.3%) patients received the planned treatment of MI-IDS. Median age was 61 (range 39-81) years and median body mass index was 24 (range 20-31) kg/m 2 . Median numbers of NACT cycles was 4 (range 3-7). Median operative time was 285 (range 124-418) minutes and median estimated blood loss was 100 (range 50-200) mL. Surgical procedures included 28 (93.3%) hysterectomy and bilateral salpingo-oophorectomy, 29 (96.6%) omentectomy, 2 (6.6%) appendectomy, 11 (36.6%) regional peritonectomy, and 1 (3.4%) bowel resection. A residual tumor of 0 cm was reached in 29 (96.6%) patients and 0.5 cm in only 1 (3.4%) case. The vast majority of patients were discharged on postoperative day 2 (range 2-3). No early postoperative complications were registered. Median time to restart chemotherapy was 20 (10-30) days and all patients successfully completed the cycles. Histological findings showed 3 (10%) complete response, 9 (30%) microscopic residual disease, and 18 (60%) evidence of macroscopic residual disease. With a median follow-up of 10.5 month, 5 peritoneal and 2 lymph nodal recurrences were observed. Psychometric test revealed moderate discomfort in the vast majority of patients (66.7%). All patients are still alive.
Conclusion
Invasive-IDS in patients with clinically complete response to NACT seems to be feasible and safe in terms of perioperative outcomes, psycho-oncological impact, and survival rate. The equivalence between MI surgery and laparotomy needs to be confirmed with a longer follow-up and a larger number of patients.
Introduction
Primary debulking surgery with optimal cytoreduction followed by platinum-based chemotherapy is the current firstline treatment in patients with advanced ovarian cancer. However, current guidelines suggest neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in specific cases to reduce tumor size and increase chances of optimal cytoreduction. The objective of IDS is to remove as much disease as possible, to improve potential response to subsequent chemotherapy.
Some randomized controlled trial studies have demonstrated that patients with optimal cytoreduction after NACT have approximately the same survival rate as patients optimally cytoreduced at primary debulking surgery.
In the last decade, we have observed an evolution in the management of ovarian cancer thanks to the introduction of minimally invasive (MI) surgery (MIS), improvement of technological supports, and development of new chemotherapeutic strategies. In this context, an increasingly important role has been attributed to laparoscopy in both apparent early-stage and advanced epithelial ovarian cancer (AEOC).
In fact, laparoscopic procedures needed to completely stage early epithelial ovarian cancer (EOC), including complete omentectomy and paraaortic lymphadenectomy as well as total abdominal hysterectomy-bilateral salpingo-oophorectomy (BSO) and peritoneal biopsies, have been shown to be as effective as standard laparotomy. Moreover, MIS allows performance of complex procedures at the level of the upper and lower abdomen, in case of single recurrence in ovarian cancer patients.
Since 2006, laparoscopy has been introduced in AEOC management to identify patients deemed unresectable at primary surgery, obtaining a histological diagnosis and avoiding a large explorative laparotomy with subsequent delayed start of NACT.
Subsequently, laparoscopy has been shown to be a valid technique to recognize partial responders to NACT to submit to IDS or to shift to a second-line therapy.
The primary objective of this study was to assess feasibility of total laparoscopic/robotic interval cytoreduction in patients with AEOC and clinical complete response to NACT. Secondary objectives were assessing perioperative outcomes, survival, and quality of life.
Materials and Methods
This is a multicentric phase II clinical trial, with the aim of assessing feasibility of MI-IDS (either by laparoscopy or robotics) after NACT in patients affected by AEOC (International Federation of Gynaecology and Obstetrics [FIGO] stage IIIC and IV).
Inclusion criteria were the following: age >18 years, histologically proven EOC, clinical complete response after NACT, and Eastern Cooperative Oncology Group (ECOG) performance status <2. Women with American Society of Anesthesiologists (ASA) score III-IV and body mass index (BMI) >40 kg/m 2 were excluded. Clinical response was assessed according to Gynecologic Cancer Intergroup (GCIG) and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Completeness of response according to 1 of the 2 criteria was sufficient to include the patient in the protocol.
Institutional review board approval was obtained and all patients signed written informed consent to be included in the protocol. The study was registered in clinicaltrials.gov (NCT02324595) and was named “MISSION” trial.
For each patient, preoperative data (type and number of cycles of NACT, prechemotherapy/postchemotherapy CA-125 serum levels, and computed tomography [CT] scan results) were collected to evaluate eligibility to a MI approach.
Perioperative outcomes (operative time, estimated blood loss, conversion to laparotomy, surgical procedures, residual tumor size, ileus, hospital discharge, days needed to restart chemotherapy, and histological findings) were registered. Early postoperative complications were registered according to the Memorial Sloan Kettering Cancer Center grading system. Data regarding prognosis, recurrence rate, pattern of recurrence, and progression-free survival were also analyzed. All patients were administered a psychometric test, General Well-Being Schedule (GWBS), to evaluate quality of life after surgery.
Study design
Patients meeting inclusion/exclusion criteria were selected to enter into the MISSION trial. All surgical procedures started with a staging laparoscopy (S-LPS) through open access at the umbilicus or Palmer point, according to surgeon’s preference and patient’s previous laparotomies. The objective of diagnostic laparoscopy was to assess preoperative findings and to consider complexity and safety of surgery in terms of technical and oncological principles. In case of evidence of partial response, surgical approach was chosen at the surgeon’s discretion.
Eligible patients were submitted to MI-IDS, either by laparoscopy or robotics, to remove all macroscopic lesions. In case of increased surgical risk or technical impossibility the case was registered as laparotomic conversion.
Surgical procedures
A careful exploration of the peritoneal cavity was the first surgical step.
A 10-mm, flexible-tip, HD 3-dimensional video-laparoscope (Olympus, Hamburg, Germany) was used to explore all peritoneal recesses. In eligible patients, for laparoscopic approach three 5-mm trocars were placed in standard position for pelvic surgery, instead for robotic procedures da Vinci Xi platform (Intuitive Surgical, Sunnyvale, CA) was used in standard surgical setting.
Cytoreduction consisted in total/radical hysterectomy, BSO, omentectomy, and pelvic or upper peritonectomy. Traditionally, we do not perform systematic pelvic and aortic lymphadenectomy, in absence of residual disease at this level, detectable at radiological imaging and/or macroscopically. Additional abdominal procedures (eg, anterior rectal resection) were performed if needed. In cases of increased surgical complexity additional trocars were placed in the right or left subcostal spaces. Advanced multifunctional instruments were used to optimize advanced surgical procedures in terms of efficacy, safety, and operative time. At the end of surgery, residual tumor was registered.
Follow-up
In accordance with National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, follow-up consisted of gynecological examination, abdominal and pelvic ultrasonography, CA-125 serum levels every 3 months, and chest and abdomen CT scan every 6 months for the first 2 years. In case of increased CA-125 serum levels and/or suspicious CT scan findings, a fluorodeoxyglucose-positron emission tomography/CT scan was requested to confirm recurrence.
The GWBS
The GWBS is a psychometric test to assess the state of general well-being of the patient. This test evaluates the subjective well-being and the level of concern over the last month. The scale determines how the person feels about her inner state rather than the outer; the 6 dimensions investigated are anxiety, depression, general health, well-being positive, self-control, and vitality. The 3 scores are: severe discomfort (range 0-60), moderate discomfort (range 61-72), and wellness (range 73-110). A psycho-oncologist administered the test within 30 days after surgery.
Materials and Methods
This is a multicentric phase II clinical trial, with the aim of assessing feasibility of MI-IDS (either by laparoscopy or robotics) after NACT in patients affected by AEOC (International Federation of Gynaecology and Obstetrics [FIGO] stage IIIC and IV).
Inclusion criteria were the following: age >18 years, histologically proven EOC, clinical complete response after NACT, and Eastern Cooperative Oncology Group (ECOG) performance status <2. Women with American Society of Anesthesiologists (ASA) score III-IV and body mass index (BMI) >40 kg/m 2 were excluded. Clinical response was assessed according to Gynecologic Cancer Intergroup (GCIG) and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Completeness of response according to 1 of the 2 criteria was sufficient to include the patient in the protocol.
Institutional review board approval was obtained and all patients signed written informed consent to be included in the protocol. The study was registered in clinicaltrials.gov (NCT02324595) and was named “MISSION” trial.
For each patient, preoperative data (type and number of cycles of NACT, prechemotherapy/postchemotherapy CA-125 serum levels, and computed tomography [CT] scan results) were collected to evaluate eligibility to a MI approach.
Perioperative outcomes (operative time, estimated blood loss, conversion to laparotomy, surgical procedures, residual tumor size, ileus, hospital discharge, days needed to restart chemotherapy, and histological findings) were registered. Early postoperative complications were registered according to the Memorial Sloan Kettering Cancer Center grading system. Data regarding prognosis, recurrence rate, pattern of recurrence, and progression-free survival were also analyzed. All patients were administered a psychometric test, General Well-Being Schedule (GWBS), to evaluate quality of life after surgery.
Study design
Patients meeting inclusion/exclusion criteria were selected to enter into the MISSION trial. All surgical procedures started with a staging laparoscopy (S-LPS) through open access at the umbilicus or Palmer point, according to surgeon’s preference and patient’s previous laparotomies. The objective of diagnostic laparoscopy was to assess preoperative findings and to consider complexity and safety of surgery in terms of technical and oncological principles. In case of evidence of partial response, surgical approach was chosen at the surgeon’s discretion.
Eligible patients were submitted to MI-IDS, either by laparoscopy or robotics, to remove all macroscopic lesions. In case of increased surgical risk or technical impossibility the case was registered as laparotomic conversion.
Surgical procedures
A careful exploration of the peritoneal cavity was the first surgical step.
A 10-mm, flexible-tip, HD 3-dimensional video-laparoscope (Olympus, Hamburg, Germany) was used to explore all peritoneal recesses. In eligible patients, for laparoscopic approach three 5-mm trocars were placed in standard position for pelvic surgery, instead for robotic procedures da Vinci Xi platform (Intuitive Surgical, Sunnyvale, CA) was used in standard surgical setting.
Cytoreduction consisted in total/radical hysterectomy, BSO, omentectomy, and pelvic or upper peritonectomy. Traditionally, we do not perform systematic pelvic and aortic lymphadenectomy, in absence of residual disease at this level, detectable at radiological imaging and/or macroscopically. Additional abdominal procedures (eg, anterior rectal resection) were performed if needed. In cases of increased surgical complexity additional trocars were placed in the right or left subcostal spaces. Advanced multifunctional instruments were used to optimize advanced surgical procedures in terms of efficacy, safety, and operative time. At the end of surgery, residual tumor was registered.
Follow-up
In accordance with National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, follow-up consisted of gynecological examination, abdominal and pelvic ultrasonography, CA-125 serum levels every 3 months, and chest and abdomen CT scan every 6 months for the first 2 years. In case of increased CA-125 serum levels and/or suspicious CT scan findings, a fluorodeoxyglucose-positron emission tomography/CT scan was requested to confirm recurrence.
The GWBS
The GWBS is a psychometric test to assess the state of general well-being of the patient. This test evaluates the subjective well-being and the level of concern over the last month. The scale determines how the person feels about her inner state rather than the outer; the 6 dimensions investigated are anxiety, depression, general health, well-being positive, self-control, and vitality. The 3 scores are: severe discomfort (range 0-60), moderate discomfort (range 61-72), and wellness (range 73-110). A psycho-oncologist administered the test within 30 days after surgery.
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