4. Management of early stage ovarian cancer

peritoneal cancer. A technical description of the operative steps and intra-peritoneal chemo-

Malignant spread of intraperitoneal tumours can occur via, local contiguous growth, noncontiguous spread along mesenteric planes, haematogenous, lymphatic or transcoelomic routes. Unlike the other routes, the transcoelomic pathway offers a rapid step change in facilitating metastasis form multiple sites from within the abdomen. The parietal peritoneum has both secretatory and absorptive functions. The omentum has an absorptive function. This has been exploited in fashioning omental flaps to minimise incidence of inguinal lymphocyst

The dynamics of peritoneal fluid is driven by secretion/adsorption by the peritoneum (in particular right diaphragmatic peritoneum), recesses formed by the peritoneal reflections, omental filtering, movement of diaphragm, negative pressure in the subdiaphragmatic region, motility of viscera on mesentry and the resultant fluctuation in pressure differential within the

The 'redistribution phenomenon' was described by Sugarbaker in relation to pseudomyxoma peritonei [1]. In this process free floating malignant cells and other debris utilise the movement of peritoneal fluid (and the ascites produced) to become redistributed throughout the peritoneal cavity. This includes the lesser sac. The absorption and filtering of the peritoneal fluid by the greater and lesser omentum can result in debris and cells, including malignant cells, becoming adherent to the omentum. This may in time result in 'omental cake' noted in advanced ovarian cancer. Another major notable site of fluid absorption and disease conglomeration is the right hemidiaphragm. Gravitational distribution explains the deposits in the Pouch of Douglas, paracolic gutters and subhepatic recesses. The mobile organs such as small bowel are spared of deposits, early in the disease, whereas fixed retroperitoneal structures such as ascending/descending colon and gastric pylorus may be affected. This would necessi-

As early as in 1934, Meigs described that 'removal of as much tumour as possible' was beneficial for survival [2]. In 1968 the British gynaecological surgeon Hudson described a pioneering technique for the resection of ovarian cancer from the pelvis [3]. Although there have been modifications, the principles have remained the same and his procedure is recognised as the 'radical oophorectomy'. This was an important step in CRS. In fact it was the seminal work of Griffith's published in 1975 which demonstrated that CRS associated with smaller residual disease, can be linked to better survival in advanced ovarian cancer [4].

therapy are outside the scope of this chapter.

236 Ovarian Cancer - From Pathogenesis to Treatment

peritoneal cavity.

tate resection of the organs.

2. Peritoneal redistribution theory and carcinomatosis

after lymphadenectomy or pelvic collection after exenteration.

3. Evolution of the concept of cytoreductive surgery

In early stage ovarian cancer, the disease is confined to the ovaries or the upper genital tract. Approximately 25% of ovarian cancer patients are diagnosed with stages 1 and 2. These women generally have an excellent prognosis, provided a full staging procedure has been performed. Proper staging allows identification of those who are truly early stage and those who might have more advanced disease. This will allow optimal recommendation regarding adjuvant chemotherapy for the apparent early stage patients [16]. The critical importance of proper staging is underlined by the long term (10 year) follow up data offered by the ICON 1 study [17]. In this study the 10 year survival varied between 56 and 78% depending on the completeness of staging [17].

Table 1 enumerates the steps in comprehensive surgical staging of suspected ovarian cancer. Even in unilateral ovarian cancer, the risk of contralateral lymph node metastasis only, is 3.5%; this is in addition to the 9.7% risk of metastasis on both sides and the 8.3% risk of ipsilateral metastasis [18]. Indeed the risk of para-aortic lymph node metastasis only is 7.1% and the risk Midline laparotomy Obtain peritoneal fluid for cytology Careful examination of all peritoneal surfaces Total abdominal hysterectomy and bilateral salpingo-oophorectomy Frozen section of ovarian mass suspicious lesions Infra-colic omentectomy Appendicectomy (for mucinous tumours) Peritoneal biopsy from diaphragmatic surface, four quadrants of the abdomen and pouch of Douglas Pelvic and para-aortic lymphadenectomy

Table 1. Staging procedure for apparent early stage ovarian cancer.

of pelvic and para-aortic lymph node metastasis is 4.3% [18]. Therefore comprehensive staging should include bilateral pelvic and para-aortic lymphadenectomy. However, this may need to be tempered by the overall clinical status of the individual patient. The single exception to this, is early stage mucinous ovarian cancer in which the risk of lymph node metastasis is minor, that omission of lymphadenectomy can be a safe option [19]. The extent of lymphadenectomy appears to correlate with survival benefit, with better outcomes being associated with lymph node counts of greater than 10 per site [18, 20].

recruited patients between 1998 and 2006. This was a time when both the surgical strategy with respect to second-look laparotomy and ultra-radical surgery as well as chemotherapy regimens

Surgical Management of Ovarian Cancer http://dx.doi.org/10.5772/intechopen.80891 239

In the EORTC 55971 study 670 patients were stratified and randomised to PDS or NACT followed by IDS groups. The selection criteria included PS score and 'severe disabling disease' but resectability of the disease by a surgeon was not a condition. The study design did not incorporate CT or laparoscopic scoring system in patient selection. At the time of surgery, in the PDS arm 61% of patients had tumour size >10 cm and 24.2% of the same in the NACT arm; the prevalence of these features at the time of randomisation was 39% in PDS and 42% in the NACT arms. This suggests that a significant proportion of patients appear to have rather aggressive disease. The median operation time was 165 min in PDS and 180 min in the NACT arms. The proportion of patients in whom microscopic clearance was achieved was 19.4% in PDS and 51.2% in the NACT arms. The splenectomy rates (5.8% in PDS, 4.0% NACT) and bowel resection rates (15.5% in PDS, 8.7% in NACT) in this study are far lower than those reported by other high volume centres at the same time [11]. The most frequent sites of residual disease were pelvis, diaphragm and abdominal peritoneum; most experienced teams would consider these sites technically resectable disease. In conjunction with other parameters of cytoreduction mentioned above, one would find it difficult to be certain that the benefits of upfront surgery could have been realised in these operatively unselected patients. The authors acknowledge that a drawback of NACT is fibrosis which might impede tumour resection [23]. The CHORUS group recruited patients with clinical/radiological stage III and IV disease between 2004 and 2010 [24]. Five-hundred and fifty-two women were randomised after stratification by tumour size, stage, PS score and tumour markers as well as prespecified chemotherapy regime (single agent carboplatin, carbotaxol or carboplatin with another agent). Patients received 6 cycles of chemotherapy in total with IDS performed after 3 cycles. The two groups were comparable with similar proportions diagnosed as stage IIIC or IV (89% in PDS and 87% in NACT arms). The median operation time was 120 minutes in both groups, which is a remarkable short time for debulking surgery in advanced ovarian cancer. This consistent with the rates of complete debulking achieved in arms, 17% in PDS and 39% in the NACT arms. Indeed the suboptimal debulking (residual disease >1 cm) was very high at 59% in the PDS and 27% in the NACT arms. These figures are out of kilt with data from high volume international centres. The median overall survival was similar in both groups, but lower than expected at 22.6 months for PDS and 24.2 months for NACT. Multivariate analysis did not identify a subgroup favouring one treatment over another. The size of the residual tumour was

Overall the QOL parameters were comparable between the two groups, except at 6 months post-treatment, the NACT group had higher scores. As expected the PDS group experienced grade 3 and 4 adverse events more frequently than the NACT group with the exception of haemorrhage. Death was more frequent in the PDS (6%) compared to the NACT (<1%) group. The administration and toxicity of chemotherapy was comparable in both groups. The authors acknowledged that the older median age, significant prevalence of poorly differentiated tumour (77%) and high prevalence (19%) of poor performance (PS 2 or 3) status might have

was rapidly evolving.

prognostic in both arms.

#### 5. Role of primary debulking surgery and neoadjuvant chemotherapy

Abundant retrospective data supported the notion of cytoreductive surgery [11, 14, 21]. The standard treatment had been PDS followed by NACT. Where the initial PDS had not resulted in 'optimal debulking' i.e. the residual disease was >1 cm in size, a second look laparotomy for further debulking after 3 cycles of NACT had been the routine practice. Randomised studies have examined this aspect and the most recent study by Rose et al. lead to the abandonment of second look laparotomy [22]. Table 2 lists the procedures required for the 'ultra-radical' cytoreductive surgery which is in addition to the essential staging procedure.

The EORTC group led by Vergote conducted the first randomised trial comparing PDS followed by adjuvant chemotherapy against IDS after 3 cycles of neoadjuvant chemotherapy [23]. The trial


Table 2. Potential procedures in 'optimal' cytoreductive surgery.

recruited patients between 1998 and 2006. This was a time when both the surgical strategy with respect to second-look laparotomy and ultra-radical surgery as well as chemotherapy regimens was rapidly evolving.

In the EORTC 55971 study 670 patients were stratified and randomised to PDS or NACT followed by IDS groups. The selection criteria included PS score and 'severe disabling disease' but resectability of the disease by a surgeon was not a condition. The study design did not incorporate CT or laparoscopic scoring system in patient selection. At the time of surgery, in the PDS arm 61% of patients had tumour size >10 cm and 24.2% of the same in the NACT arm; the prevalence of these features at the time of randomisation was 39% in PDS and 42% in the NACT arms. This suggests that a significant proportion of patients appear to have rather aggressive disease. The median operation time was 165 min in PDS and 180 min in the NACT arms. The proportion of patients in whom microscopic clearance was achieved was 19.4% in PDS and 51.2% in the NACT arms. The splenectomy rates (5.8% in PDS, 4.0% NACT) and bowel resection rates (15.5% in PDS, 8.7% in NACT) in this study are far lower than those reported by other high volume centres at the same time [11]. The most frequent sites of residual disease were pelvis, diaphragm and abdominal peritoneum; most experienced teams would consider these sites technically resectable disease. In conjunction with other parameters of cytoreduction mentioned above, one would find it difficult to be certain that the benefits of upfront surgery could have been realised in these operatively unselected patients. The authors acknowledge that a drawback of NACT is fibrosis which might impede tumour resection [23].

of pelvic and para-aortic lymph node metastasis is 4.3% [18]. Therefore comprehensive staging should include bilateral pelvic and para-aortic lymphadenectomy. However, this may need to be tempered by the overall clinical status of the individual patient. The single exception to this, is early stage mucinous ovarian cancer in which the risk of lymph node metastasis is minor, that omission of lymphadenectomy can be a safe option [19]. The extent of lymphadenectomy appears to correlate with survival benefit, with better outcomes being associated with lymph

Peritoneal biopsy from diaphragmatic surface, four quadrants of the abdomen and pouch of Douglas

5. Role of primary debulking surgery and neoadjuvant chemotherapy

cytoreductive surgery which is in addition to the essential staging procedure.

Diaphragmatic peritoneal stripping segmental full-thickness resection of the diaphragm

Resection of suspicious or enlarged retroperitoneal lymph nodes Resection of pleural disease hycardiophrenic lymph nodes

Table 2. Potential procedures in 'optimal' cytoreductive surgery.

Abundant retrospective data supported the notion of cytoreductive surgery [11, 14, 21]. The standard treatment had been PDS followed by NACT. Where the initial PDS had not resulted in 'optimal debulking' i.e. the residual disease was >1 cm in size, a second look laparotomy for further debulking after 3 cycles of NACT had been the routine practice. Randomised studies have examined this aspect and the most recent study by Rose et al. lead to the abandonment of second look laparotomy [22]. Table 2 lists the procedures required for the 'ultra-radical'

The EORTC group led by Vergote conducted the first randomised trial comparing PDS followed by adjuvant chemotherapy against IDS after 3 cycles of neoadjuvant chemotherapy [23]. The trial

In addition to the above, the following procedures may be required to obtain microscopic clearance of the disease.

node counts of greater than 10 per site [18, 20].

Total abdominal hysterectomy and bilateral salpingo-oophorectomy

Table 1. Staging procedure for apparent early stage ovarian cancer.

Frozen section of ovarian mass suspicious lesions

Midline laparotomy

Infra-colic omentectomy

Small bowel resection Large bowel resection Intestinal stoma formation Supracolic omentectomy

Cholecystectomy

Splenectomy distal pancreatectomy Segmental or lobular liver resection

Obtain peritoneal fluid for cytology Careful examination of all peritoneal surfaces

Appendicectomy (for mucinous tumours)

238 Ovarian Cancer - From Pathogenesis to Treatment

Pelvic and para-aortic lymphadenectomy

The CHORUS group recruited patients with clinical/radiological stage III and IV disease between 2004 and 2010 [24]. Five-hundred and fifty-two women were randomised after stratification by tumour size, stage, PS score and tumour markers as well as prespecified chemotherapy regime (single agent carboplatin, carbotaxol or carboplatin with another agent). Patients received 6 cycles of chemotherapy in total with IDS performed after 3 cycles. The two groups were comparable with similar proportions diagnosed as stage IIIC or IV (89% in PDS and 87% in NACT arms). The median operation time was 120 minutes in both groups, which is a remarkable short time for debulking surgery in advanced ovarian cancer. This consistent with the rates of complete debulking achieved in arms, 17% in PDS and 39% in the NACT arms. Indeed the suboptimal debulking (residual disease >1 cm) was very high at 59% in the PDS and 27% in the NACT arms. These figures are out of kilt with data from high volume international centres. The median overall survival was similar in both groups, but lower than expected at 22.6 months for PDS and 24.2 months for NACT. Multivariate analysis did not identify a subgroup favouring one treatment over another. The size of the residual tumour was prognostic in both arms.

Overall the QOL parameters were comparable between the two groups, except at 6 months post-treatment, the NACT group had higher scores. As expected the PDS group experienced grade 3 and 4 adverse events more frequently than the NACT group with the exception of haemorrhage. Death was more frequent in the PDS (6%) compared to the NACT (<1%) group. The administration and toxicity of chemotherapy was comparable in both groups. The authors acknowledged that the older median age, significant prevalence of poorly differentiated tumour (77%) and high prevalence (19%) of poor performance (PS 2 or 3) status might have contributed to the less than expected overall survival. Indeed only 56% of patients received combination chemotherapy in their first cycle if their PS was 2–3 but this increased to 72% if their PS was 0–1. This differential has been recognised in the design of the currently recruiting TRUST trial.

This is the first prospective randomised study seeking to verify a finding of an exploratory analysis of EORTC 55971, which stated that for a subgroup of patients with large tumour volumes, NACT lead to fewer morbidites and significantly better overall survival [29]. Therefore the selection of patients for this SCORPION trial was guided by laparoscopic predictive index (PI) [30, 31].Those patients with PI of >8 and < 12 were deemed eligible. In this study 55 were randomly assigned to each arm. None of the patients were subjected to a 'second-look' laparotomy. The cytoreductive rate to nil macroscopic disease was 45.5% in PDS arm and 57.7% in NACT arm. There was no significant difference in terms of the distribution of the residual disease between the two arms—these were military disease on small bowel serosa, hepatic hilum and nodal disease above the superior mesenteric artery. Upper abdominal procedures were carried out in 100% in the PDS and 42.3% in NACT arms. The surgical complexity score was significantly higher in the PDS arm. As a result PDS was associated with longer operating times and higher blood loss; this was accompanied by a mortality rate of 3.6% in the PDS and none in the NACT arms. Three patients in the NACT arm were not submitted for surgery due to disease progression. Many of the generic and specific parameters of QOL measures were in favour of NACT; interestingly cognitive and social functioning showed longitudinal improvement with the PDS group only. The oncological outcomes are awaited. In due course, the findings of this study may complement those of the on-going TRUST trial. The AGO initiated multicenter international trial, TRUST study (NCT02828618), aims to address many of the short comings identified in the EORTC 55971 and the CHORUS studies. These are addressed by applying selection criteria with regards to the patients, disease and surgical team characteristics. Unlike any of the earlier RCTs in evaluating the timing of surgery in advanced epithelial ovarian cancer, involvement in the TRUST trial will entail an audit of the participating centres prior to study engagement. This ensures that the surgeon(s), surgical team and the relevant infrastructure are in place to deliver the most optimal cytoreductive surgery. The study is expected to complete recruitment in 2023. The outcomes of interest include surgical complications at 28 days, clinical outcomes at 1 year, QOL as well as oncolog-

Surgical Management of Ovarian Cancer http://dx.doi.org/10.5772/intechopen.80891 241

The two most important prognostic characteristics in ovarian cancer are comprehensive staging and optimal cytoreductive surgery [21]. Disease morphology (as predicted by cross sectional imaging and/or laparoscopic assessment), physiological fitness of the patient and the skill set of the surgeon or surgical team are the three key domain determining the resectability. Since we have long abandoned the concept of second look laparotomy, it is important that where risk of residual exists, we must seek alternatives to primary debulking surgery, otherwise the patient may be dealt with a treatment strategy which is overall suboptimal. Therefore can biochemical, molecular imaging or endoscopic assessment help predict optimal surgery? This subject is a vast area and it will be briefly reviewed here in the context of cytoreductive

ical measures at 5 years.

6. Predictors of optimal cytoreduction

surgery for advanced ovarian cancer.

Indeed only 77% in the PDS and 79% in the NACT arms completed the allocated treatment strategy.

Both EORTC 55971 and CHORUS trials have been heavily criticised [23, 24]. Indeed one would have to question the rigour with which the peritoneal residual disease might have been assessed in these two studies. For instance the incidence of peritoneal disease within the omental bursa is in excess of 60% [25]. Adequate exploration of the omental bursa is an advanced technique requiring assessment of coeliac nodes, caudate lobe, supragastric lesser omentum and the recesses on the left lateral aspect. One cannot be certain if these steps had been implemented in the earlier RCTs. Thus leading to inaccurate estimation of residual disease. The potential issue of surgeon bias in estimating residual disease has been highlighted in a radiological referencing study [26].

Indeed three further RCTs are examining the question of primary debulking surgery versus neoadjuvant chemotherapy [27, 28]. In fact all three trials include physiological status of the patient in their inclusion criteria. This feature was lacking in the CHORUS trial; EORTC 55971 excluded patients with PS 3 or 'serious disabling disease'.

The Japanese studies (JCOG0602) and the Italian (SCORPION trial) studies have published the peri-operative outcomes [27, 28]. As expected both of these studies demonstrate fewer perioperative complications, shorter length of stay and smaller blood loss after neoadjuvant chemotherapy compared to primary debulking surgery.

The Japanese multicentre study recruited 301 between 2006 and 2011. In total, 8 cycles of carboplatin and paclitaxol were administered. Those patients with a residual tumour of >1 cm following PDS were offered IDS after 4 cycles of adjuvant chemotherapy. This is despite the publication of GOG152 by Rose et al. in 2004 demonstrating no advantage to second look laparotomy after a maximal effort at PDS [22]. Another peculiarity of this study is the interval of more than 4 years between recruitment of the last patient and submission of the manuscript.

The 'optimal debulking' rate in this study, defined as residual tumour of <1 cm, was 82% in the NACT and 37% in PDS group; when all treated patients are taken into account, including the second-look laparotomy, then the optimal debulking rate changes to 71 and 63% in the NACT and PDS arms respectively [28]. The grade 3–4 complications were less frequent after NACT compared to PDS. Resection of 'abdominal organs' and 'distant metastasis' were more common after PDS. Curiously the duration of main surgery was longer in NACT (302 versus 240 min); this may be explained by the significantly higher rates of pelvic and para-aortic lymphadenectomy in the NACT arm (pelvic LND 72.3% versus 27.2%; para-aortic LND 49.2% versus 11.6%) [28].

In the phase 3 Italian study, Fagotti and colleagues set out to investigate the best strategy for managing patients with high tumour load [27]. Patients were recruited between 2011 and 2014. This is the first prospective randomised study seeking to verify a finding of an exploratory analysis of EORTC 55971, which stated that for a subgroup of patients with large tumour volumes, NACT lead to fewer morbidites and significantly better overall survival [29]. Therefore the selection of patients for this SCORPION trial was guided by laparoscopic predictive index (PI) [30, 31].Those patients with PI of >8 and < 12 were deemed eligible. In this study 55 were randomly assigned to each arm. None of the patients were subjected to a 'second-look' laparotomy. The cytoreductive rate to nil macroscopic disease was 45.5% in PDS arm and 57.7% in NACT arm. There was no significant difference in terms of the distribution of the residual disease between the two arms—these were military disease on small bowel serosa, hepatic hilum and nodal disease above the superior mesenteric artery. Upper abdominal procedures were carried out in 100% in the PDS and 42.3% in NACT arms. The surgical complexity score was significantly higher in the PDS arm. As a result PDS was associated with longer operating times and higher blood loss; this was accompanied by a mortality rate of 3.6% in the PDS and none in the NACT arms. Three patients in the NACT arm were not submitted for surgery due to disease progression. Many of the generic and specific parameters of QOL measures were in favour of NACT; interestingly cognitive and social functioning showed longitudinal improvement with the PDS group only. The oncological outcomes are awaited. In due course, the findings of this study may complement those of the on-going TRUST trial.

The AGO initiated multicenter international trial, TRUST study (NCT02828618), aims to address many of the short comings identified in the EORTC 55971 and the CHORUS studies. These are addressed by applying selection criteria with regards to the patients, disease and surgical team characteristics. Unlike any of the earlier RCTs in evaluating the timing of surgery in advanced epithelial ovarian cancer, involvement in the TRUST trial will entail an audit of the participating centres prior to study engagement. This ensures that the surgeon(s), surgical team and the relevant infrastructure are in place to deliver the most optimal cytoreductive surgery. The study is expected to complete recruitment in 2023. The outcomes of interest include surgical complications at 28 days, clinical outcomes at 1 year, QOL as well as oncological measures at 5 years.
