**2. Evolution of gynaecological oncology surgery**

Gynaecological oncological surgery has a rather interesting evolution. This is evident in the management of uterine and vulval cancers, where there has been transition to less aggressive surgery. In vulval cancer the utilisation of sentinel node biopsy plays a major role to reduce the morbidity associated with lymphadenectomy, whilst the application of minimal access surgery in the management of uterine cancer, has ensured faster surgical recovery and significantly shortened length of hospital stay. In contrast, the surgical approach to ovarian cancer has gone through an inverse transition in the last twenty years and despite all efforts to optimise


**93**

*The Role of Ultra-Radical Surgery in the Management of Advanced Ovarian Cancer: State or Art*

medical management throughout the introduction of targeted therapies, surgery has

Minimally invasive surgery can be performed when the disease is confined to the primary site (stage I ovarian cancer). In widespread disease, total hysterectomy with bilateral salpingo-oophorectomy, infracolic omentectomy and systematic pelvic/para-aortic lymphadenectomy are required in order to determine the need for adjuvant treatment and complete full surgical staging. However, the latter does not regularly apply to ovarian cancer since 80% of patients with ovarian cancer present with advanced disease (stages III and IV) Advanced disease implies a short time for management and treatment; as usually the cancer has spread to the upper abdomen,

Before effective treatment can be offered for ovarian cancer, the disease needs to be correctly staged. This can be achieved by means of radiological modalities or exploratory laparoscopy, or a combination of both. Ovarian cancer staging is

Historically the treatment of ovarian cancer was primary debulking surgery

When to perform the debulking surgery in advanced ovarian cancer (AOC) has been the cause of debate and controversy for almost a decade [14]. The supporters of primary debulking surgery (PDS) advocate significantly better overall survival (OS) and progression-free survival (PFS) rates, whilst the opponents argue higher surgical morbidity and often fatal disease [14–17]. It is well recognised that for each 10% increase in maximal cytoreduction, there is an associated 5.5% increase in median survival [14, 18, 19]. However, in the vast majority of cases, complete debulking is associated with multivisceral resection which requires extensive surgi-

Neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) have

In 2010, Vergote et al. conducted a phase III randomised control trial (EORTC) [9] where neoadjuvant chemotherapy followed by interval debulking surgery (IDS) was compared with upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy. This trial demonstrated that survival in both arms was similar (29 and 30 months, respectively), however there was less morbidity in patients who had chemotherapy first, mainly in those cases deemed difficult to operate [9]. The same findings were corroborated by the CHORUS phase III randomised controlled trial [20] that was used as a benchmark to justify the role of neoadjuvant chemotherapy in patients who were not candidates for upfront surgery. The survival remained 22 and 24 months, respectively. There have been many debates since the publication of these two RCTs, with regards to survival outcome and the need for a more radical

The Trial on Radical Upfront Surgery in Advanced Ovarian Cancer (TRUST) will hopefully enlighten the adequate management of patients with AOC and will also establish predictive and prognostic biomarkers of operability and survival,

followed by chemotherapy, whenever it was deemed to be feasible.

cal expertise, training and infrastructural support.

been considered as means to reduce surgical morbidity.

surgical approach, in order to achieve complete cytoreduction.

remained the mainstay of treatment and has progressively more radical [12]. In ovarian cancer, a midline laparotomy is usually performed to fully access anatomical structures in the pelvis and intra-abdominal cavity. With a midline laparotomy the patient will have a longer hospital stay, as opposed to laparoscopy,

*DOI: http://dx.doi.org/10.5772/intechopen.97638*

mandating multi-visceral resection.

presented in **Table 1** [13].

**3.1 Background**

**3. Ovarian cancer treatment**

or robotic surgery.

**Table 1.**

*Ovarian cancer staging (Society of Gynaecologic Oncology).*

*The Role of Ultra-Radical Surgery in the Management of Advanced Ovarian Cancer: State or Art DOI: http://dx.doi.org/10.5772/intechopen.97638*

medical management throughout the introduction of targeted therapies, surgery has remained the mainstay of treatment and has progressively more radical [12].

In ovarian cancer, a midline laparotomy is usually performed to fully access anatomical structures in the pelvis and intra-abdominal cavity. With a midline laparotomy the patient will have a longer hospital stay, as opposed to laparoscopy, or robotic surgery.

Minimally invasive surgery can be performed when the disease is confined to the primary site (stage I ovarian cancer). In widespread disease, total hysterectomy with bilateral salpingo-oophorectomy, infracolic omentectomy and systematic pelvic/para-aortic lymphadenectomy are required in order to determine the need for adjuvant treatment and complete full surgical staging. However, the latter does not regularly apply to ovarian cancer since 80% of patients with ovarian cancer present with advanced disease (stages III and IV) Advanced disease implies a short time for management and treatment; as usually the cancer has spread to the upper abdomen, mandating multi-visceral resection.

Before effective treatment can be offered for ovarian cancer, the disease needs to be correctly staged. This can be achieved by means of radiological modalities or exploratory laparoscopy, or a combination of both. Ovarian cancer staging is presented in **Table 1** [13].

### **3. Ovarian cancer treatment**

### **3.1 Background**

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**2. Evolution of gynaecological oncology surgery**

management of advanced ovarian cancer.

confirmed this finding. Debulking surgery is a multi-visceral operation involving the pelvis, lower and upper abdomen, aiming at a complete resection (CR) of all visible disease to a microscopic cellular level [8–11]. This is also called cytoreductive surgery. We present the latest surgical developments in ultra-radical surgery for the

Gynaecological oncological surgery has a rather interesting evolution. This is evident in the management of uterine and vulval cancers, where there has been transition to less aggressive surgery. In vulval cancer the utilisation of sentinel node biopsy plays a major role to reduce the morbidity associated with lymphadenectomy, whilst the application of minimal access surgery in the management of uterine cancer, has ensured faster surgical recovery and significantly shortened length of hospital stay. In contrast, the surgical approach to ovarian cancer has gone through an inverse transition in the last twenty years and despite all efforts to optimise

Carcinoma of the Ovary

IC1. Surgical spill

peritoneal cancer

Stage I: Tumour confined to ovaries

IC. Tumour limited to 1 or both ovaries

IB. Tumour involves both ovaries otherwise like IA

IC2. Capsule rupture before surgery or tumour on ovarian surface

IIA. Extension and/or implant on uterus and/or fallopian tubes

IC3. Malignant cells in the ascites or peritoneal washings

IIB. Extension to other pelvic intraperitoneal tissues

IIIA1. Positive retroperitoneal lymph nodes only

to the retroperitoneal lymph nodes

extension to capsule of liver/spleen.

extension to capsule of liver/spleen.

IVA. Pleural effusion with positive cytology

Stage IV: Distant metastasis excluding peritoneal metastasis

*Ovarian cancer staging (Society of Gynaecologic Oncology).*

inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

IIIA1(i). Metastasis ≤10 mm IIIA1(ii). Metastasis >10 mm

nodes

IA. Tumour limited to 1 ovary, capsule intact, no tumour on surface, negative washings

Stage II: Tumour involves 1 or both ovaries with pelvic extension (below the pelvic brim) or primary

IIIA. Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the pelvis

Stage III: Tumour involves 1 or both ovaries, confirmed spread to extra-pelvic peritoneum and/or metastasis

IIIA2. Microscopic, extra-pelvic (above the brim) peritoneal involvement ± positive retroperitoneal lymph

IIIB. Macroscopic, extra-pelvic, peritoneal metastasis ≤2 cm ± positive retroperitoneal lymph nodes. Includes

IIIC. Macroscopic, extra-pelvic, peritoneal metastasis >2 cm ± positive retroperitoneal lymph nodes. Includes

IVB. Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal organs (including

**92**

**Table 1.**

Historically the treatment of ovarian cancer was primary debulking surgery followed by chemotherapy, whenever it was deemed to be feasible.

When to perform the debulking surgery in advanced ovarian cancer (AOC) has been the cause of debate and controversy for almost a decade [14]. The supporters of primary debulking surgery (PDS) advocate significantly better overall survival (OS) and progression-free survival (PFS) rates, whilst the opponents argue higher surgical morbidity and often fatal disease [14–17]. It is well recognised that for each 10% increase in maximal cytoreduction, there is an associated 5.5% increase in median survival [14, 18, 19]. However, in the vast majority of cases, complete debulking is associated with multivisceral resection which requires extensive surgical expertise, training and infrastructural support.

Neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) have been considered as means to reduce surgical morbidity.

In 2010, Vergote et al. conducted a phase III randomised control trial (EORTC) [9] where neoadjuvant chemotherapy followed by interval debulking surgery (IDS) was compared with upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy. This trial demonstrated that survival in both arms was similar (29 and 30 months, respectively), however there was less morbidity in patients who had chemotherapy first, mainly in those cases deemed difficult to operate [9]. The same findings were corroborated by the CHORUS phase III randomised controlled trial [20] that was used as a benchmark to justify the role of neoadjuvant chemotherapy in patients who were not candidates for upfront surgery. The survival remained 22 and 24 months, respectively. There have been many debates since the publication of these two RCTs, with regards to survival outcome and the need for a more radical surgical approach, in order to achieve complete cytoreduction.

The Trial on Radical Upfront Surgery in Advanced Ovarian Cancer (TRUST) will hopefully enlighten the adequate management of patients with AOC and will also establish predictive and prognostic biomarkers of operability and survival,

as well as identify valid fragility scores for vulnerable patients, with the aim of obtaining a more individualised surgical approach [14, 21].

Radical procedures to resect advanced ovarian cancer have been reported since 1965 [22]. In the late 70′s the "peritoneal compartment" concept was developed, with the introduction of en-bloc resection of pelvic organs and the surrounding peritoneum [23]. The logic of en-bloc resection is based on the notion of ovarian cancer as a peritoneal disease, where the peritoneum acts as a dissemination conduit but also limiting the spread. In fact, it is less frequent to see dissemination to the retroperitoneal organs. The en-bloc resection aims at seeking dissection planes within healthy tissue, minimising tumour manipulation and avoiding cutting through cancer tissue. Rapid tumour growth is usually supported by significant angiogenesis, primarily at the tumour periphery. As a result, there is a distortion of normal anatomy and findings of aberrant vascularisation. Therefore, a surgical technique that finds cleavage planes beyond the tumour growth is likely to reduce blood loss.

Visceral-Peritoneal Debulking (VPD) is offered to patients with stage III–IV ovarian cancer [24]. VPD applies the concept of en-bloc resection to all abdominal quadrants.

Maximal cytoreductive surgery aims at total macroscopic tumour clearance combined with platinum-based chemotherapy, these being the cornerstone of modern primary epithelial ovarian cancer (EOC) management [25]. Numerous prospective and retrospective series have demonstrated a strong positive association between total macroscopic tumour clearance rates and survival [25, 26]. A study comparing a surgical population, with a population who received chemotherapy alone (in 2 different cancer centres) showed that 43.8% of patients who had surgery died versus 86% of patients in the chemotherapy group [25].

Cytoreductive surgery is a standard part of national and international guidelines [25, 27, 28], hence surgical management with maximal therapeutic effort is the aim of treatment, even for patients with a higher tumour load, as survival of the patients has been clearly demonstrated [25].

### **3.2 Patient selection**

The mainstay of treatment is a holistic approach to the patient's care. The patient needs to fully understand the benefits, risks and alternatives to surgery. Consent for this procedure needs to be carefully considered and fully informed.

### **3.3 Clinical assessment**

The patient needs to be assessed with regards to their ability to walk and carry out ordinary activities independently, which includes climbing a flight of stairs. The advice of the anaesthetist is valuable, and cardiopulmonary exercise testing (CPET) may also be required to determine the anaerobic threshold of the patient prior to major surgery [24].

Demographic characteristics which have to be considered when selecting patients are age, previous abdominal surgery, ASA score, presence of ascites, preoperative Ca125, preoperative level of haemoglobin, albumin, FIGO stage, histological cancer type [29].

The triage process of patients for debulking includes:

a.a suitable WHO Performance Status (PS) at the preoperative assessment.

b.absence of lung or multiple parenchymal liver metastases on the CT scan.

**95**

*The Role of Ultra-Radical Surgery in the Management of Advanced Ovarian Cancer: State or Art*

c. exploratory laparoscopy did not demonstrate small bowel serosal disease or

Liu et al. [31, 32] reported that more than a quarter of women with advanced ovarian cancer treated with neoadjuvant chemotherapy (NACT) do not ever undergo cytoreductive surgery. Significant risk factors contributing to the inability to undergo surgery were advanced age, low albumin levels, frailty scores and extensive disease of predominantly high-grade serous histology. The main reasons identified were extent of disease not amenable to surgery or lack of response to NACT, patient co-morbidities preventing surgery and extent of disease. The patients who did not have debulking surgery, had an over 3-fold increase in mortality of any

In patients with advanced disease, there is a strong rationale to personalise the surgical treatment and implement predictive and prognostic scores [31]. The aim is to allocate the right treatment to the right patient, in order to avoid unnecessary

Appreciation of potential impact on the quality of life (QoL) has to be thor-

A pre-operative CT scan for the thorax, abdomen and pelvis with contrast is essential. The patients with disease progression with lung metastasis or three or more liver segments involvement should be triaged for neo-adjuvant chemotherapy strategy [24]. Tozzi et al. has shown that exploratory laparoscopy added to the CT scan could potentially identify porta hepatis peritoneal disease [33] as well as small bowel serosal involvement. Several advantages of the exploratory laparoscopy have been reported, amongst which a correct diagnosis based on the histology of the tissue biopsy, accurate evaluation of the spread of the disease, including the spread of small military disease, a better selection of the patients for ultra-radical surgery and a better planning of resources in view of the surgery [34]. The authors concluded that this combination of investigations is of a high reliability, and encouraged surgical outcomes [33, 34].

Following confirmation of suitability for surgery based on the CT scan, it is recommended to consider an exploratory laparoscopy to rule out diffuse small bowel serosa deposits and porta hepatis encasement [24]. There are controversies around this approach, however it has been demonstrated [24] that the use of Palmer's point and Hasson's technique to enter the abdomen is an easy and safe technique. This is a short procedure, very informative, allowing a thorough assessment of the intraabdominal cavity, and helps in avoiding a laparotomy if the chances of no residual

A systematic approach is required, and this is performed by assessing in system-

a.In the *upper abdomen* the diaphragm, liver, with its Glisson's capsule, falciform ligament, ligamentum teres, Morison's pouch, the stomach, lesser omentum also known as gastro-hepatic ligament, spleen, tail of pancreas, porta hepatis also known as hepato-dudenal ligament, foramen of Winslow, and the coeliac

cause, compared to those who had surgery at some point [31, 32].

oughly assessed and balanced against survival benefit.

*DOI: http://dx.doi.org/10.5772/intechopen.97638*

porta hepatis encasement [30].

iatrogenic damage [31].

**3.5 Diagnostic laparoscopy**

disease are unlikely.

atic manner.

**3.6 Systematic abdominal exploration**

**3.4 Investigations**

*The Role of Ultra-Radical Surgery in the Management of Advanced Ovarian Cancer: State or Art DOI: http://dx.doi.org/10.5772/intechopen.97638*

c. exploratory laparoscopy did not demonstrate small bowel serosal disease or porta hepatis encasement [30].

Liu et al. [31, 32] reported that more than a quarter of women with advanced ovarian cancer treated with neoadjuvant chemotherapy (NACT) do not ever undergo cytoreductive surgery. Significant risk factors contributing to the inability to undergo surgery were advanced age, low albumin levels, frailty scores and extensive disease of predominantly high-grade serous histology. The main reasons identified were extent of disease not amenable to surgery or lack of response to NACT, patient co-morbidities preventing surgery and extent of disease. The patients who did not have debulking surgery, had an over 3-fold increase in mortality of any cause, compared to those who had surgery at some point [31, 32].

In patients with advanced disease, there is a strong rationale to personalise the surgical treatment and implement predictive and prognostic scores [31]. The aim is to allocate the right treatment to the right patient, in order to avoid unnecessary iatrogenic damage [31].

Appreciation of potential impact on the quality of life (QoL) has to be thoroughly assessed and balanced against survival benefit.

### **3.4 Investigations**

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

growth is likely to reduce blood loss.

has been clearly demonstrated [25].

**3.2 Patient selection**

**3.3 Clinical assessment**

major surgery [24].

cancer type [29].

quadrants.

obtaining a more individualised surgical approach [14, 21].

died versus 86% of patients in the chemotherapy group [25].

this procedure needs to be carefully considered and fully informed.

The triage process of patients for debulking includes:

as well as identify valid fragility scores for vulnerable patients, with the aim of

Radical procedures to resect advanced ovarian cancer have been reported since 1965 [22]. In the late 70′s the "peritoneal compartment" concept was developed, with the introduction of en-bloc resection of pelvic organs and the surrounding peritoneum [23]. The logic of en-bloc resection is based on the notion of ovarian cancer as a peritoneal disease, where the peritoneum acts as a dissemination conduit but also limiting the spread. In fact, it is less frequent to see dissemination to the retroperitoneal organs. The en-bloc resection aims at seeking dissection planes within healthy tissue, minimising tumour manipulation and avoiding cutting through cancer tissue. Rapid tumour growth is usually supported by significant angiogenesis, primarily at the tumour periphery. As a result, there is a distortion of normal anatomy and findings of aberrant vascularisation. Therefore, a surgical technique that finds cleavage planes beyond the tumour

Visceral-Peritoneal Debulking (VPD) is offered to patients with stage III–IV ovarian cancer [24]. VPD applies the concept of en-bloc resection to all abdominal

Maximal cytoreductive surgery aims at total macroscopic tumour clearance combined with platinum-based chemotherapy, these being the cornerstone of modern primary epithelial ovarian cancer (EOC) management [25]. Numerous prospective and retrospective series have demonstrated a strong positive association between total macroscopic tumour clearance rates and survival [25, 26]. A study comparing a surgical population, with a population who received chemotherapy alone (in 2 different cancer centres) showed that 43.8% of patients who had surgery

Cytoreductive surgery is a standard part of national and international guidelines [25, 27, 28], hence surgical management with maximal therapeutic effort is the aim of treatment, even for patients with a higher tumour load, as survival of the patients

The mainstay of treatment is a holistic approach to the patient's care. The patient needs to fully understand the benefits, risks and alternatives to surgery. Consent for

The patient needs to be assessed with regards to their ability to walk and carry out ordinary activities independently, which includes climbing a flight of stairs. The advice of the anaesthetist is valuable, and cardiopulmonary exercise testing (CPET) may also be required to determine the anaerobic threshold of the patient prior to

Demographic characteristics which have to be considered when selecting patients are age, previous abdominal surgery, ASA score, presence of ascites, preoperative Ca125, preoperative level of haemoglobin, albumin, FIGO stage, histological

a.a suitable WHO Performance Status (PS) at the preoperative assessment.

b.absence of lung or multiple parenchymal liver metastases on the CT scan.

**94**

A pre-operative CT scan for the thorax, abdomen and pelvis with contrast is essential. The patients with disease progression with lung metastasis or three or more liver segments involvement should be triaged for neo-adjuvant chemotherapy strategy [24]. Tozzi et al. has shown that exploratory laparoscopy added to the CT scan could potentially identify porta hepatis peritoneal disease [33] as well as small bowel serosal involvement. Several advantages of the exploratory laparoscopy have been reported, amongst which a correct diagnosis based on the histology of the tissue biopsy, accurate evaluation of the spread of the disease, including the spread of small military disease, a better selection of the patients for ultra-radical surgery and a better planning of resources in view of the surgery [34]. The authors concluded that this combination of investigations is of a high reliability, and encouraged surgical outcomes [33, 34].

### **3.5 Diagnostic laparoscopy**

Following confirmation of suitability for surgery based on the CT scan, it is recommended to consider an exploratory laparoscopy to rule out diffuse small bowel serosa deposits and porta hepatis encasement [24]. There are controversies around this approach, however it has been demonstrated [24] that the use of Palmer's point and Hasson's technique to enter the abdomen is an easy and safe technique. This is a short procedure, very informative, allowing a thorough assessment of the intraabdominal cavity, and helps in avoiding a laparotomy if the chances of no residual disease are unlikely.

### **3.6 Systematic abdominal exploration**

A systematic approach is required, and this is performed by assessing in systematic manner.

a.In the *upper abdomen* the diaphragm, liver, with its Glisson's capsule, falciform ligament, ligamentum teres, Morison's pouch, the stomach, lesser omentum also known as gastro-hepatic ligament, spleen, tail of pancreas, porta hepatis also known as hepato-dudenal ligament, foramen of Winslow, and the coeliac

trunk needs to be assessed. The latter two can be examined by palpation at laparotomy only, and this represents a limiting factor.


After all these assessments the conclusion can be withdrawn as whether the surgery will be beneficial and results in no residual disease. This often requires an intra-operative multi-disciplinary consultation between two senior gynaecological oncologist.
