Outcomes of Laparoscopic Optimal Interval Cytoreduction Surgery (LOICS) in Patients with Advanced Ovarian Cancers Having Low Burden Disease

Abstract

Laparoscopy has been increasingly utilised for cytoreduction surgery in patients with early ovarian cancers. The present study tries to assess the feasibility of laparoscopic interval cytoreduction surgery (LOICS) in patients with advanced ovarian cancer (AOC) having low burden residual disease. A retrospective study of was done of AOC’s who underwent LOICS between 2010 and 2014. Epithelial ovarian cancer patients who underwent interval cytoreduction surgery were included and analysed for short-term and long-term outcomes. In all, 36 patients with stage III ovarian cancers were included in the analysis. Twenty-two (61.1%) were grade 3 and 14 (38.8%) were grade 2, and no patient had grade 1 tumour. Stage wise majority were stage IIIC (94.4%) followed by 2 (5.5%) in stage IIIA. There was 1 postoperative complication (2.5%) and no intraoperative complications. Median time to discharge and to start chemotherapy was 5 days and 23 days respectively. After a median follow-up of 60 months, 3 patients (8.3%) were lost to follow-up and the remaining 33 patients were analysed for survival outcomes. The overall survival (OS) and recurrence-free survival (RFS) were 58.3% and 36.1% respectively. The median RFS and OS were 24 months and 51 months, respectively. Most recurrences involved the peritoneum (82.6%), and 5 patients (21.7%) had nodal recurrence alone. Laparoscopic optimal interval cytoreduction is feasible in patients with advanced ovarian cancers provided the disease burden permits optimal surgery, especially in centres with expertise in complex laparoscopic procedures.

Introduction

Laparoscopy has been shown to have role in gynaecological cancers including endometrial and early ovarian cancers [1–3]. Surgery remains the cornerstone of treatment in ovarian cancers, it is essential to achieve a complete cytoreduction with no macroscopic residual disease. In advanced ovarian cancers (stages III and IV), the volume of disease and complexity of surgery may preclude the use of laparoscopy for complete cytoreduction. The extent of surgery decreases significantly in patients with a very good response to chemotherapy. Laparoscopic cytoreduction is a technically demanding procedure with scarce literature on its utilisation in advanced ovarian cancers.

Patients with advanced ovarian cancers have been traditionally staged with a midline laparotomy, incision extending from pubic symphysis to xiphisternum. The goal of surgery being complete cytoreduction with no residual macroscopic disease. However primary cytoreduction is feasible in only 20–50% of patients [4–6]. There is an increasing trend towards interval cytoreduction in patients with advanced ovarian cancers (AOC), to decrease the bulk of disease and make optimal cytoreduction feasible. Interval cytoreduction (IC) has shown its non-inferiority to primary cytoreduction in AOC (stage III, IV) in atleast 2 randomised clinical trials [4, 7]. Neoadjuvant chemotherapy helps in increasing the number of optimal cytoreduction’s performed with a reduction in overall surgical morbidity [4]. Many of these patients will have an excellent response to chemotherapy with complete clinical response seen in 20–30% of patients [8]. They may be good candidates for minimal access cytoreduction surgery (MACS). The aim of the present study was to assess the feasibility of laparoscopic cytoreduction in patients with advanced ovarian cancer (AOC) with low tumour burden postneoadjuvant chemotherapy.

Material and Methods

This was a retrospective study of patients with advanced ovarian cancers patients operated from January 2010 to December 2014. Details of patients with epithelial ovarian cancers having FIGO (International Federation of Gynecology and Obstetrics) stage III or above on presentation and who underwent laparoscopic optimal interval cytoreduction surgery (LOCS), after neoadjuvant chemotherapy was obtained from surgical database and medical record department. All patients underwent contrast enhanced computed tomography (CECT) scan and CA-125 levels at diagnosis to stage the disease and after chemotherapy to assess response. Radiologic complete response on post NACT scan was not a criterion but normalisation of CA125 levels following chemotherapy (less than 37 U/ml) was a mandatory criterion for inclusion. Patients who had undergone suboptimal primary surgery elsewhere or deemed inoperable and subsequently given neoadjuvant chemotherapy (NACT) were also included. Exclusion criteria were presence of disease in critical areas of the abdomen such as hepatophrenic ligament, lesser sac, porta hepatis and splenophrenic ligament in postneoadjuvant scan, not accessible by laparoscopy. LOCS included bilateral salpingo-oophorectomy, hysterectomy, omentectomy, resection of residual peritoneal metastasis (involved field peritonectomy) and aspiration of ascites if present. Pelvic and retroperitoneal lymphadenectomy were done only if suspicious nodes were present on preoperative imaging or to achieve a complete cytoreduction.

During laparoscopic surgery, patients were placed in French position with Trendelenburg tilt. The operating surgeon stood on the right side of patient for the pelvic steps and in between the patients’ legs for the para-aortic nodal dissection and omentectomy. A 10 mm 30° laparoscope was introduced at the supra umbilical site with open technique and pneumoperitoneum was established. Under direct vision, 2 trocars were positioned: one 12 mm and one 5 mm, 2 cm above and medial to the anterior superior iliac spine along the spino-umbilical line on right and left side respectively. Two more 5 mm trocars were placed in mid clavicular line at the level of umbilicus. Entire peritoneum was inspected to look for any suspicious lesions and ascites if present was aspirated. Pelvic procedures, including hysterectomy, bilateral salpingo-oophorectomy and pelvic node dissection (in case of suspicious nodes), were completed. If retroperitoneal lymph node dissection was planned, another 10-mm camera port was placed in the suprapubic region.

Preoperative information including age of the patient at diagnosis, body mass index (BMI), histological type, grade of disease, FIGO stage, type and number of cycles of neoadjuvant chemotherapy were collected. The intraoperative data analysed included estimated blood loss, operating time, extent of surgery performed and any intraoperative complications. Postoperatively, final histopathology and presence of any residual disease was noted. Adjuvant chemotherapy was planned after discussion in the multidisciplinary meeting depending upon number of cycles and type of neoadjuvant chemotherapy. Patients were followed up for any recurrence. On follow-up, pelvic examination, abdominal ultrasound and CA-125 levels were performed every 3 months during the first 2 years after treatment, then at 6-monthly intervals for the next 3 years and annually thereafter. Long-term outcomes including recurrence-free and overall survival were calculated from date of surgery to date of recurrence or death, respectively.

Statistics

Continuous variables are presented as median with range. Categorical variables are presented as number of cases or percentages. Overall survival was estimated from the date of surgery to death and progression-free survival from the date of surgery to the first appearance of recurrence. Median overall survival and progression-free survival curves were calculated and presented by the Kaplan–Meier curves.

Results

A total of 622 patients underwent cytoreduction surgery between 2011 and 2014; out of which, 61 patients (9.8%) underwent laparoscopic cytoreduction surgery. Seventeen patients in stage I and 4 patients in stage II were excluded. Forty patients in FIGO stage III remained from the 61 who underwent laparoscopic CRS. One patient with germ cell histology and 3 patients who underwent primary cytoreduction were excluded and 36 patients with serous epithelial ovarian cancer were included in the final analysis. The median age was 50 years (range, 31–75) and the median BMI was 23 kg/m² (range, 14.5–36). Four patients in the group had undergone previous laparotomy for ovarian malignancy with suboptimal surgery and were included in the analysis. 61.1% patients had grade 3 tumours, 38.9% had grade 2 tumours and none had grade 1 tumour. Based on the initial prechemotherapy clinical and imaging evaluation, 94.4% were in FIGO stage IIIC, 5.6% in FIGO stage IIIA no patient in FIGO stage IIIB (Table 1). Overall, 3 to 8 cycles of chemotherapy were given. In total, 34 patients (94.4%) received 3 cycles of NACT and two (5.6%) received more than 3 cycles before surgery. Final histopathological examination (HPE) showed complete pathologic response in 7 patients (19.4%) (Table 2).

Table 1.

Clinical and pathological features

Characteristic	Number, n = 36	Percentage/range
Median age (range)	50	(31–75)
Median BMI (range)	23	(14.5–36)
Previous laparotomy	4	11.1%
ASA score
I	30	83.3%
II	6	16.7%
Histologic type (WHO)
Epithelial serous	36	100%
Grading
1	0	0
2	14	38.9%
3	22	61.1%
Median serum Ca-125 level at diagnosis, (UI/ml) (range)	1121	(3–4221)
Stage at diagnosis
IIIA	2	5.6%
IIIB	0	0
IIIC	34	94.4%
Surgery
Interval	36	100%

Table 2.

Chemotherapy given and response postchemotherapy

All cases		Number,  n = 36	Percentage
1. Chemotherapy cycles	3 cycles	34	94.4%
	More than 3 cycles	2	5.6%
2. Type of chemotherapy	Carboplatin paclitaxel (either weekly or 3 weekly)	34	94.4%
	Carboplatin – gemcitabine	1	2.8%
	Single agent carboplatin	1	2.8%
3. Pathological response	Complete	7	19.4%
	Partial	29	80.6%

All patients underwent omentectomy and 32 hysterectomy (88.8%) (others had undergone hysterectomy earlier for an unrelated cause). Regional peritonectomy (mostly douglassectomy) was done in 6 patients (16.6%), of which 2 had low-volume residual disease in right subdiaphragmatic peritoneum, resected at laparoscopy. Six (16.6%) patients underwent pelvic, 4 (11.1%) underwent para-aortic lymphadenectomy and 3 (8.3%) patients required appendectomy. No patient had macroscopic residual disease at the completion of cytoreduction. The median operating time was 178 min (range 90–300 min) and median estimated blood loss was 180 ml (range, 50–500 ml). One patient required intraoperative blood transfusion. Median time to discharge was 5 days (3–8 days) and the median time to start chemotherapy was 23 days (14–40 days) (Table 3). There was only one postoperative complication. This patient had bilious content in the drain on the 3rd postoperative day. She underwent re-exploration laparotomy and a jejunal perforation was noted at the site of adhesiolysis, which was managed by primary suturing. Thereafter, her postoperative course was uneventful.

Table 3.

Intraoperative and postoperative characteristics

All cases	Number, n = 36	Percentage/range
Components of surgery:
Hysterectomy	32	88.8%
Omentectomy	36	100%
Regional peritonectomy	6	16.7%
Pelvic/para-aortic lymphadenectomy	8	22.2%
Appendectomy	3	8.3%
Median OT time in minutes (range)	178	90–300
Median discharge time, days (range)	5	3–8
Intraoperative blood transfusion	1	2.7%
Median blood loss, ml (range)	189	50–500
Intraoperative complication	0	0%
Postoperative complication (%)	1	2.8%
Estimated median TTC, days (range)	23	14–40

OT operation time, TTC time to start chemotherapy

At a median follow-up of 60 months, 3 patients (8.3%) were lost to follow-up and the remaining 33 were analysed for survival outcomes. A total of 23 patients (69.7%) had recurrence of which 15 (45.4%) died of disease. The overall survival was 54.5% and the progression-free survival was 30.3%. The median progression-free survival was 24 months and median overall survival was 51 months. Figure 1 shows the Kaplan-Meir curves for recurrence-free and overall survival. Most recurrences were isolated peritoneal disease or in combination with other sites (18 patients, 78.3%). Amongst these 18, 4 patients developed distant metastases, two developed both parenchymal liver with lung metastases, brain or neck node metastases were each seen in one patient. The remaining 14 patients had isolated peritoneal recurrence, majority had diffuse peritoneal metastasis (both above and below the pelvic brim) with ascites (10 patients), 2 had predominantly pelvic peritoneal recurrence whilst the other 2 had mostly upper abdomen recurrence.

Fig. 1.

Kaplan–Meier curves for overall survival and progression-free survival

Five patients (21.7%) had nodal recurrence alone. Four of them had suspicious pelvic nodes on preoperative imaging, hence had undergone pelvic with paraaortic lymph node dissection; of these four, three had positive pelvic nodes on the final histopathology report. The fifth patient had no enlarged nodes on imaging and did not undergo nodal dissection.

Discussion

Studies have shown the equivalence of laparoscopy in staging of patients with early ovarian cancers [9–11]. When compared to laparotomy, benefits of laparoscopy in oncogynaecologic procedures include decreased pain, lesser surgical site infections, shorter hospital stay, early return to activity and lesser incidence of postoperative adhesions [3]. With recent advances in laparoscopic technology and camera systems, laparoscopic cytoreduction has also been attempted in AOC [12, 13]. Though laparoscopy was traditionally used for pelvic resections in gynaecological cancers, it has gained acceptance for resection of disease in upper abdomen including removal of bulky omental disease and diaphragmatic implants [14]. In the present study, we could achieve a complete cytoreduction in all the 36 patients in whom LOCS was attempted. The median time to discharge and time to start chemotherapy were 5 and 23 days, respectively. There was one major postoperative complication requiring re-exploration from which the patient recovered. The overall survival was 54.5% and the progression-free survival was 30.3%. We found acceptable short-term and long-term outcomes following LOCS in our study.

Few studies over the last decade have tried to assess the role of laparoscopy in AOC in both interval [8, 15–20] and primary settings [21] and have found encouraging results. Two small studies, assessing the feasibility of LOCS in AOC, postNACT had shown promising short-term outcomes [15, 16]. A study of 21 patients comparing LOCS with open cytoreduction found a statistically insignificant decrease in recurrence-free survival but an increase in cancer specific mortality [17]. The Multicentre phase II, MISSION study [15] assessing the feasibility and early complication rate of minimal access, interval debulking surgery (IDS) in stage III–IV epithelial ovarian cancer (EOC) following NACT included only patients with clinically complete response to chemotherapy, ASA score of I and II and BMI (Body mass index) of less than 40 kg/m². They found it to be safe in terms of perioperative outcomes, survival rate and the quality of life after surgery. Interestingly in this study, 12% of the total 28.2% eligible patients were converted to open surgery. Despite clinical complete response following chemotherapy, the authors felt laparoscopic cytoreduction in that subset would have made the surgical procedure unsafe, either from a technical or an oncological point of view. Thus, in 42% of eligible patients, CT scan could not predict suitability for LOCS. The prospective International Mission study [8] with 127 patients enrolled across 5 centres also found acceptable short- and long-term outcomes. The conversion rate to laparotomy was 3.9% in patients initially deemed feasible for LOCS and only 4.7% of patients had short-term complications.

One of the main oncological advantages for laparoscopic surgery includes early initiation of adjuvant chemotherapy. The mean time to start chemotherapy in our study was 23 days, which is comparable to other studies on laparoscopic debulking surgery [8, 15]. Considering the detrimental effect of delay in initiating chemotherapy on prognosis [22], LOCS may be beneficial if complete cytoreduction is achieved. The US national cancer database analysis [19] comparing minimal access (MA) to open cytoreduction in AOC showed similar 3-year survival with comparable re-admission rates, perioperative deaths and shortened hospital stay. A recently published meta-analysis [23] between MA and open cytoreduction including 3231 patients (majority being from the US national cancer database) from 6 studies found no significant increase in more than grade 2 complications with comparable oncological outcomes in the MA group. All these studies were in interval setting and there is only one study in primary setting which found LOCS as feasible with acceptable success rates (82%) [21].

After a median follow-up of 60 months, 3 patients (8.3%) were lost to follow-up. The overall survival (OS) was 54.5% and the progression-free survival (PFS) was 30.3%. The median PFS was 24 months and median OS was 51 months. Our study has one of the longest follow-up amongst other similar studies reported in literature. The international mission study reported their results after a median follow-up of 37 months and had a 5-year projected survival of 52.6% (Table 4). The recurrence pattern in our study suggests a predominantly diffuse peritoneal recurrence on follow-up. Amongst the patients who developed nodal recurrence, 3 patients had a node positive disease on final HPE, thus indicating a higher nodal tumour burden.

Table 4.

Comparison with other studies on laparoscopic surgery in advanced ovarian cancers

Study	Surgery	Number of patients	Recurrence-free survival (%)	Overall survival (%)	Median follow-up (months)
Fanning et al. (primary laparoscopic cytoreduction) [21]	L	11	-	100	12
Melamed et al. (3-year survival)[19]	O	2621	-	52.6	32
	L	450	-	47.5
Favero et al. [17]	O	11	-	100	36
	L	10	-	80	20
Gueli Alletti et al. [15]	L	30	Not reached	-	10.5
A Fagotti et al. (5-year survival) [8]	L	127	-	52.6	37
Present study	L	36	30.3%	54.5%	60

L laparoscopic, O open

LOCS has few limitations. The major limitation being inability to assess hidden areas such as hepatophrenic ligament, lesser sac, porta hepatis, splenophrenic ligament and small bowel interloop spaces [24]. Adhesions and scarring due to chemotherapy may add to the difficulty in visualisation of these areas. However, the chance of isolated residual disease in these areas with an excellent response elsewhere in the abdomen, though known, would be rare. Widespread acceptance of LOCS is also limited by the ongoing debate between involved field versus total peritonectomy during IDS, as it would be difficult to perform a total peritonectomy by laparoscopy. Few studies have shown better outcome with total peritonectomy [25, 26], although there is no level 1 evidence to support the same. Complications occurring during laparoscopic surgery and the ability to tackle them by laparoscopy are also a limiting factor, restricting its adoption in low volume centres. In our study, only one patient (2.5%) had more than grade 2 complication (intestinal perforation) identified postoperatively and underwent laparotomy for the same. Other studies have shown postoperative complications ranging from 0 to 20% [15, 16] with overall pooled proportion of 3.1% in a meta-analysis [19]. Only one small study reported a higher postoperative complication in LOCS (20%) as compared to its open arm [17].

We did not perform bowel resections or extensive diaphragmatic peritonectomy as part of LOCS, as most of these patients underwent laparotomy following initial diagnostic laparoscopy and were excluded from the study. Although possible to remove nodules over diaphragm using laparoscopy, extensive peritonectomy for a plaque like residual disease may be challenging, considering the postchemotherapy scarring. Additionally diaphragmatic movements hinder dissection and limited vision of the posterior aspects of the diaphragm. In our experience, many a times, bowel which appears to be adherent to the adnexal mass, may be salvaged with meticulous dissection at laparotomy, whilst the same may not be possible at laparoscopy thus avoiding unnecessary bowel resections. The present study had a few limitations, mainly an inherent bias associated with a retrospective study. The small sample size, inability to assess quality of life and absence of comparative open arm make it difficult to arrive at a powerful recommendation. However, considering the high disease burden in patients with similar stage who underwent open surgery, the comparison would not have been accurate unless a randomised trial is performed. The role of routine comprehensive pelvic and retroperitoneal lymphadenectomy in advanced epithelial ovarian cancers has been unclear with a fair share of proponents and critics. The NCCN guidelines [30] recommends lymphadenectomy in the presence of suspicious/enlarged nodes in preoperative imaging or during surgery. The LION trial [31] recommends lymphadenectomy in AOC only if complete macroscopic cytoreduction has been achieved and there were suspicious nodes at diagnosis or during the procedure.

Betrian et al. [33] analysed the disease-free survival (DFS) in advanced ovarian cancers according to the chemotherapy response scores. The response to chemotherapy was scored as 1, 2 or 3. Scores of 1 and 2 indicate minimal response and 3 as good response. Patients with chemotherapy response score of 3 showed improved median disease-free survival. The median disease-free survival in patients with complete or near-complete response (score 3) was 28.3 months as against 16.3 months in patients with chemotherapy response score 1–2. The disease-free survival in our study is nearly the same as that published by Betrian et al.

In our opinion, all patients with stage III EOC should be subjected to a diagnostic laparoscopy at the time of surgery. Depending upon the extent and location of tumour deposits, feasibility of a laparoscopic complete cytoreduction should be assessed. Preoperative imaging studies may help to triage these patients initially but the ultimate tool to select patients for LOCS is a diagnostic laparoscopy performed at the time of definitive surgery. Recently, few studies have been published showing feasibility of laparoscopic cytoreduction with HIPEC in patients with peritoneal carcinomatosis [27–29]. The ongoing multicentre, randomised, non-inferiority LANCE trial (Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy) [32] compares minimal access surgery with laparotomy in women with advanced stage high-grade epithelial ovarian cancers will probably provide some definitive conclusions to LOCS. Presently laparoscopic cytoreduction should be performed in centres with expertise in complex minimal access procedures. More widespread applicability of LOCS will depend on ability of surgeon to perform advanced laparoscopic procedures and more robust evidence in terms of oncological safety.

Conclusion

Laparoscopic cytoreduction is feasible in patients with advanced ovarian cancers provided the disease burden permits optimal surgery. They should be only performed in high-volume centres with expertise in complex laparoscopic procedures.

Author Contribution

Vikas Gupta, R. Rajagopalan Iyer, T Subramanyeshwar Rao and KVVN Raju were involved in conception and design of the work, acquisition, analysis and interpretation of data for the work, writing of the manuscript and gave approval of the final version. Syed Murtaza Ahmed and Manan Shah were involved in acquisition, analysis and interpretation of data for the work.

Data Availability

The datasets analysed during the current study are available from the corresponding author on request.

Declarations

The data of the present study were collected in the course of common clinical practice, and accordingly, the signed informed consent was obtained from each patient for any surgical and clinical procedure. The study protocol was in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments. Because this was a retrospective study, formal consent for this study is not required and no approval of the institutional research committee was needed.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.