4. Surgical considerations in the patient with ROC

A general impression is that secondary cytoreductive surgery for ROC is more commonly routine practice in the USA and parts of Europe, and less so in the UK. This is evidenced by the fact that most reports on the role or impact of such surgery have come from non-UK centres. Almost all reports on surgery for ROC refer to recurrent EOC and not to the non-epithelial types or borderline cancers. Furthermore, the reports on surgical management mostly focus on the first recurrence after primary treatment, rather than the second or third recurrence. The NCCN Guidelines [15] state that secondary cytoreduction can be considered in patients with recurrent ovarian cancer (1) (detected at) more than 6–12 months after completion of initial chemotherapy, (2) who do not have ascites and (3) who have an isolated recurrence (or few foci) of disease which can be completely resected.

In clinical practice, there are different scenarios in which the surgical option for ROC needs to be considered.

Broadly these may be described as:

improved prognosis has been challenged [8, 9]. With regard to the common EOC, recurrent disease may not be associated with high levels of CA 125, it may be associated with a normal level or with a rise within the normal range, and there are other non-cancer explanations for a rising level post-treatment. In a recent trial, it was concluded that treating recurrences (early) with chemotherapy based on rising tumour marker(s) was not associated with increased survival but was associated with a reduced quality of life [8–10]. It is important to note, however, that secondary cytoreductive surgery was not a standard of care in this trial. On the other hand, there is some evidence that early surgical intervention in asymptomatic patients might increase the rate of complete secondary cytoreductive surgery [11, 12]. This then is an argument for post-treatment surveillance by serial tumour marker estimations. With a rise in CA125 noted, the median time to clinical evidence of relapse is 2–6 months. There are no national guidelines in the UK regarding the post-treatment use of serial assessment of serum markers which is often to allay patient anxiety or as part of a trial protocol. Likewise in the USA, the national society, Society of Gynecologic Oncologists (SGO) [13], has not unequivo-

cally endorsed routine post-treatment surveillance using serum tumour marker(s).

In 2000, a collaboration of major cancer groups published criteria to help standardise radiologic interpretation of response to treatment of disease (cancer), which are known as Response Evaluation Criteria in Solid Tumours (RECIST) [14]. In the non-acute routine clinical followup, there is variation in the use of imaging, the modality used and the frequency of imaging. Patients on clinical trials typically will have regular imaging as part of the trial. There are no national guidelines in the UK. The National Comprehensive Cancer Network (NCCN) does not stipulate or recommend routine imaging after primary treatment of OC [15]. In most centres, imaging will be performed if there are symptoms (e.g. weight loss, abdominal distension) or signs (palpable pelvic mass). In the UK, the usual imaging will be a CT scan of chest abdomen and pelvis; in other centres FDG-PET may be performed instead of, or in addition to, CT. Practices also vary in the timing of imaging in relation to rising serum tumour marker(s) including rising levels within the normal range, and levels that exceed the normal range. However, as noted above, early treatment of recurrence with chemotherapy is reportedly not in the patient's best interest whereas earlier surgical intervention may be [8, 9, 11, 12]. In the symptomatic patient with, for example, suspected bowel obstruction, a number of imaging tests will be performed in an effort to confirm the diagnosis, to determine the cause, and to aid

When deciding on the management of a patient with ROC whose initial management has been in another institution, in many cases it is recommended that there be a review of histology and relevant imaging, and details of the prior surgery. The operative reports should be obtained

A general impression is that secondary cytoreductive surgery for ROC is more commonly routine practice in the USA and parts of Europe, and less so in the UK. This is evidenced by the

rather than reliance on a brief summary in patient correspondence.

4. Surgical considerations in the patient with ROC

3.3. Imaging

274 Ovarian Cancer - From Pathogenesis to Treatment

in the management decisions.


There are many published reports on the role and impact of secondary cytoreductive surgery in ROC. Many are from single institutions, often with small numbers, and with minimal quality of life data and, as yet, there are no published studies providing level I evidence on the impact of secondary cytoreductive surgery on overall survival in ROC. So although the best evidence at present is not yet confirmed in trials, there are three randomised controlled trials assessing the role of surgery in ROC, only one of which has just released preliminary data. These are DESKTOP III, SOCceR and GOG 213, in all of which an eligibility criterion is platinum-sensitive EOC [16–18].


Assessing surgery in ROC involves considering the can do/should do approaches and the best to worse scenario from surgery; allied considerations include the timing of surgery, the goal of surgery, morbidity and mortality from surgery and impact on quality of life issues (QoL). From the patient's perspective when deciding on major surgery, the main considerations are whether there are symptoms or not, the impact of surgery on symptoms and on survival, morbidity and mortality from surgery, quality of life issues (QoL), and response to further chemotherapy or other agents. It is more often easy to decide who not to operate on electively for recurrent disease. This decision is based on disease-associated and patient-associated factors. The former include—disease-free interval, platinum-sensitive/platinum-resistant disease, histology, site or sites of recurrent disease, with and without ascites; the latter include whether the recurrence is symptomatic or asymptomatic, QoL and performance status. There are also surgeon-related factors which relate mostly to the surgical philosophy in the management of recurrent disease —in essence whether to operate on the asymptomatic patient or not, and whether to remove bulk disease only or to plan to achieve complete surgical cytoreduction (CSC) where at end of surgery there is no gross visible disease. As will be discussed, the evidence is very much in favour of CSC to maximise patient benefit as defined by overall survival. The surgeon and/or other members of the oncology team also need to discuss the treatment alternatives with the patient.

#### 4.1. Patient selection criteria for secondary cytoreductive surgery

Major surgery for recurrent ovarian cancer is associated with morbidity and mortality reportedly from minimal up to 88.8 and 5.5%, respectively [19]. Given the heterogeneity in the patient population and the variation in surgical practice, this perhaps is not surprising. However, it also attests to lack of appropriate reliable criteria for case selection. The goals for elective surgery for recurrent disease in the abdomen/pelvis are to (1) improve overall survival, (2) minimise surgical morbidity and (3) improve QoL. The data on QoL following secondary surgical cytoreduction are, however, sparse.

place on each factor in each individual case. Intuitively one would consider that long diseasefree interval, good performance status (before elective surgery) and complete surgical cytoreduction would be favourable for improved survival. A number of predictive models been proposed to improve case selection for secondary complete cytoreductive surgery as

Surgery for Recurrent Ovarian Cancer http://dx.doi.org/10.5772/intechopen.71587 277

The original DESKTOP OVAR I trial which involved 25 institutions (Arbeitsgemeinschaft Gynaekologische Onkologie [AGO] Descriptive Evaluation of preoperative Selection (K) Criteria for Operability in recurrent ovarian cancer trial) reported that the main predictor for overall survival was complete surgical resection, which was achieved in 49.8% of patients [23]. Patients with nonepithelial ovarian cancer, those with low malignant potential tumours, and those undergoing palliative surgery (as opposed to cytoreductive surgery) were excluded [23]. In the subsequent DESKTOP I Trial [24], in patients with platinum-sensitive disease, the authors reported a median survival of 45 months compared to 19 months in those with complete and incomplete surgical resection, and those (in other studies) treated with chemotherapy alone. Of interest, they also reported that peritoneal carcinomatosis was not a negative factor if complete resection was achieved emphasising that carcinomatosis was not a contraindication to surgery and that complete resection despite the presence of carcinomatosis improved survival [24]. From this study, three prognostic factors for complete resection were identified: (1) good performance status (defined as) on the ECOG criteria [25] (European Cooperative Oncology Group), (2) complete resection at first surgery for primary disease and (3) ascites volume less than 500 ml. These were grouped as the AGO score and defined as positive if all three were present. These were subsequently validated in the DESKTOP II study [26]. It is of interest that imaging was relevant to their predictive model only for measuring volume of ascites and not for the number, size or anatomic location of tumour recurrences. Intuitively it might be considered that carcinomatosis in the setting of recurrent disease would be a contra-indication to secondary surgery and that resection of such disease would not improve overall survival. Laparoscopic assessment was not

these patients benefit most from surgery (Tables 2 and 3).

Initial second-line chemotherapy before secondary surgery (yes/no)

Table 1. Prognostic factors for improved survival after cytoreductive surgery for ROC.

Residual disease after primary surgery (complete vs. incomplete) Disease-free interval (platinum-sensitive, platinum-resistant)

Primary disease

Recurrent disease

Initial FIGO stage (early versus late)

Platinum-free interval

Performance status

Serum CA 125

Number of sites of recurrence

Ascites (present or absent (or <500 ml))

Tumour burden/largest tumour mass

The rationale for surgery might be considered as an extension of the surgical philosophy in the management of primary ovarian cancer—that complete surgical cytoreduction and combination chemotherapy provides the best therapy to achieve increased overall survival. Furthermore, in the setting of recurrent disease and the known poorer response of ovarian cancer to second-line therapy compared to first-line therapy, one can argue that cytoreduction may have a more important role in recurrent cancer. Indeed, most of the evidence on clinical trials in the chemotherapy-only approach to ROC report median survival of about 18 months in platinumsensitive disease and about 12 months in platinum-resistant disease [20]. Patients with ROC who undergo CSC have improved survival compared to those treated with chemotherapy alone, but selection bias is likely as those unfit for surgery, for example, will most often receive chemotherapy.

Repeatedly studies report that overall survival is improved with surgical cytoreduction in patients with platinum-sensitive disease but only in patients with CSC and in those with minimal residual disease. In essence the surgical goal in regard to cytoreduction for first recurrence is the same as for primary disease—complete resection. From these studies, a number of factors emerge which are associated with improved survival (Table 1). These factors are not dissimilar to those reported as important factors in improved outcome from chemotherapy for ROC [21, 22]. What is less clear from the reports is how much weight to

#### Primary disease

the patient's perspective when deciding on major surgery, the main considerations are whether there are symptoms or not, the impact of surgery on symptoms and on survival, morbidity and mortality from surgery, quality of life issues (QoL), and response to further chemotherapy or other agents. It is more often easy to decide who not to operate on electively for recurrent disease. This decision is based on disease-associated and patient-associated factors. The former include—disease-free interval, platinum-sensitive/platinum-resistant disease, histology, site or sites of recurrent disease, with and without ascites; the latter include whether the recurrence is symptomatic or asymptomatic, QoL and performance status. There are also surgeon-related factors which relate mostly to the surgical philosophy in the management of recurrent disease —in essence whether to operate on the asymptomatic patient or not, and whether to remove bulk disease only or to plan to achieve complete surgical cytoreduction (CSC) where at end of surgery there is no gross visible disease. As will be discussed, the evidence is very much in favour of CSC to maximise patient benefit as defined by overall survival. The surgeon and/or other members of the oncology team also need to discuss the treatment alternatives

Major surgery for recurrent ovarian cancer is associated with morbidity and mortality reportedly from minimal up to 88.8 and 5.5%, respectively [19]. Given the heterogeneity in the patient population and the variation in surgical practice, this perhaps is not surprising. However, it also attests to lack of appropriate reliable criteria for case selection. The goals for elective surgery for recurrent disease in the abdomen/pelvis are to (1) improve overall survival, (2) minimise surgical morbidity and (3) improve QoL. The data on QoL following secondary

The rationale for surgery might be considered as an extension of the surgical philosophy in the management of primary ovarian cancer—that complete surgical cytoreduction and combination chemotherapy provides the best therapy to achieve increased overall survival. Furthermore, in the setting of recurrent disease and the known poorer response of ovarian cancer to second-line therapy compared to first-line therapy, one can argue that cytoreduction may have a more important role in recurrent cancer. Indeed, most of the evidence on clinical trials in the chemotherapy-only approach to ROC report median survival of about 18 months in platinumsensitive disease and about 12 months in platinum-resistant disease [20]. Patients with ROC who undergo CSC have improved survival compared to those treated with chemotherapy alone, but selection bias is likely as those unfit for surgery, for example, will most often receive

Repeatedly studies report that overall survival is improved with surgical cytoreduction in patients with platinum-sensitive disease but only in patients with CSC and in those with minimal residual disease. In essence the surgical goal in regard to cytoreduction for first recurrence is the same as for primary disease—complete resection. From these studies, a number of factors emerge which are associated with improved survival (Table 1). These factors are not dissimilar to those reported as important factors in improved outcome from chemotherapy for ROC [21, 22]. What is less clear from the reports is how much weight to

4.1. Patient selection criteria for secondary cytoreductive surgery

surgical cytoreduction are, however, sparse.

with the patient.

276 Ovarian Cancer - From Pathogenesis to Treatment

chemotherapy.

Initial FIGO stage (early versus late) Residual disease after primary surgery (complete vs. incomplete) Disease-free interval (platinum-sensitive, platinum-resistant) Platinum-free interval Recurrent disease

Performance status Number of sites of recurrence Ascites (present or absent (or <500 ml)) Serum CA 125 Tumour burden/largest tumour mass Initial second-line chemotherapy before secondary surgery (yes/no)

Table 1. Prognostic factors for improved survival after cytoreductive surgery for ROC.

place on each factor in each individual case. Intuitively one would consider that long diseasefree interval, good performance status (before elective surgery) and complete surgical cytoreduction would be favourable for improved survival. A number of predictive models been proposed to improve case selection for secondary complete cytoreductive surgery as these patients benefit most from surgery (Tables 2 and 3).

The original DESKTOP OVAR I trial which involved 25 institutions (Arbeitsgemeinschaft Gynaekologische Onkologie [AGO] Descriptive Evaluation of preoperative Selection (K) Criteria for Operability in recurrent ovarian cancer trial) reported that the main predictor for overall survival was complete surgical resection, which was achieved in 49.8% of patients [23]. Patients with nonepithelial ovarian cancer, those with low malignant potential tumours, and those undergoing palliative surgery (as opposed to cytoreductive surgery) were excluded [23]. In the subsequent DESKTOP I Trial [24], in patients with platinum-sensitive disease, the authors reported a median survival of 45 months compared to 19 months in those with complete and incomplete surgical resection, and those (in other studies) treated with chemotherapy alone. Of interest, they also reported that peritoneal carcinomatosis was not a negative factor if complete resection was achieved emphasising that carcinomatosis was not a contraindication to surgery and that complete resection despite the presence of carcinomatosis improved survival [24]. From this study, three prognostic factors for complete resection were identified: (1) good performance status (defined as) on the ECOG criteria [25] (European Cooperative Oncology Group), (2) complete resection at first surgery for primary disease and (3) ascites volume less than 500 ml. These were grouped as the AGO score and defined as positive if all three were present. These were subsequently validated in the DESKTOP II study [26]. It is of interest that imaging was relevant to their predictive model only for measuring volume of ascites and not for the number, size or anatomic location of tumour recurrences. Intuitively it might be considered that carcinomatosis in the setting of recurrent disease would be a contra-indication to secondary surgery and that resection of such disease would not improve overall survival. Laparoscopic assessment was not

#### AGO Score [23, 24]


#### SeC-Score [34]


#### Minaguchi Proposal [37]


#### Memorial Sloan Kettering Proposal [40, 41]

	- DFI 6–12 m surgery for single site recurrence, possibly if more than one site
	- DFI 12–30 m surgery for one or more sites of disease; possible surgery if carcinomatosis
	- DFI > 30 m surgery for single site, multiple sites, and carcinomatosis

Table 2. Predictive models for complete surgical Cytoreduction in recurrent ovarian cancer (based on platinum-sensitive disease).

[none, 0.1–1 cm (2): >1 cm (4)]. Low and high-risk models were defined. The difference in median survival between the two groups (63.0 and 19.1 months) was highly significant, and they reported that complete surgical resection was the goal if survival gain was to be maximised. Their model, however, is arguably not straightforward. Note is made that the results of imaging had more influence on decision making (ascites and number of sites of disease) than in the AGO predictive model. In contrast, other studies have reported an improved outcome with single site versus

.

Surgery for Recurrent Ovarian Cancer http://dx.doi.org/10.5772/intechopen.71587 279

Tian et al. [33] reported on another model in an attempt to better define those patients with recurrent disease most likely to benefit from cytoreductive surgery. Six criteria were identified initial FIGO stage, residual disease after primary cytoreduction, progression-free interval, ECOG performance status, CA125 and ascites. They categorised patients into low and high-risk groups based on the score. Compared to other models they reported lower complete cytoreduction rates (53.4% in the low risk group and 20.1% in the high-risk group) than in DESKTOP I. Another group proposed another model which they defined as the SeC-score using four criteria [34]: preoperative CA 125, pre-operative HE4, ascites and residual disease at primary surgery. They reported a sensitivity and specificity of 82 and 83%. This is one of the few reports to comment on the potential value of CA125, and in a previous study an elevated CA 125 was reported as a negative prognostic factor [35]. Angioloi et al. were the only group reporting on the newer tumour marker, HE4, and the only one in which performance status was not considered. Again in this model, as in the AGO model, the role of pre-operative imaging was essentially only to measure the volume of ascites. Frederick et al. [36] reported in a study on 62 patients with prior complete cytoreduction and platinum-sensitive disease that the only pre-operative factor predicting prolonged survival was a CA125 of less than 250 U/ml which was associated with complete surgical cytoreduction. A Japanese group proposed another model using four criteria [37]—treatment-free interval > 12 months, single site disease, absence of distant metastasis(es) and performance status of 0. Depending on the number of favourable factors, the outcome in

multiple site recurrence [31] and with a DFI of 24 months or more [32].

Primary disease Early FIGO stage

Long DFI/PFI Recurrent disease

No ascites

CA125\*\*\*

\*

Good performance status

Number of sites of recurrence\*\* Maximum tumour dimension

\*\*The fewer the better the outcome. \*\*\*Normal versus abnormal level.

Complete cytoreduction at primary surgery

Based on data from platinum-sensitive epithelial ovarian cancer.

Table 3. Predictive factors for complete surgical cytoreduction (CSC) in ROC\*

terms of complete resection, and overall survival were significantly different.

part of the protocol. There is some suggestion that open laparoscopy may help in case selection —Plotti et al. [27] reported 34 of 38 patients who had a laparoscopy suggesting suitability for surgery subsequently underwent complete secondary cytoreduction. Although there are some randomised data on the use of laparoscopy to determine complete surgical cytoreduction in primary EOC, there are no such data for recurrent disease [28, 29].

A subsequent analysis based on pooled data from an international collaborative cohort [30] reported a scoring system ranging from 0 to 8: progression-free interval < 23.1 months (2), ascites (1), multiple sites of recurrence (1), residual disease after secondary cytoreductive surgery


Table 3. Predictive factors for complete surgical cytoreduction (CSC) in ROC\* .

part of the protocol. There is some suggestion that open laparoscopy may help in case selection —Plotti et al. [27] reported 34 of 38 patients who had a laparoscopy suggesting suitability for surgery subsequently underwent complete secondary cytoreduction. Although there are some randomised data on the use of laparoscopy to determine complete surgical cytoreduction in

Table 2. Predictive models for complete surgical Cytoreduction in recurrent ovarian cancer (based on platinum-sensitive

A subsequent analysis based on pooled data from an international collaborative cohort [30] reported a scoring system ranging from 0 to 8: progression-free interval < 23.1 months (2), ascites (1), multiple sites of recurrence (1), residual disease after secondary cytoreductive surgery

primary EOC, there are no such data for recurrent disease [28, 29].

• DFI 6–12 m surgery for single site recurrence, possibly if more than one site

• DFI > 30 m surgery for single site, multiple sites, and carcinomatosis

• DFI 12–30 m surgery for one or more sites of disease; possible surgery if carcinomatosis

AGO Score [23, 24]

1. Initial stage

1. Complete surgical cytoreduction at primary surgery

2. Residual disease after primary cytoreductive surgery

4. Residual tumour volume at completion of primary surgery

2. No distant metastases (versus distant metastasis) 3. Single versus more than one site of recurrence

Memorial Sloan Kettering Proposal [40, 41]

2. Single or more than one site of recurrence 3. Presence or absence of carcinomatosis

2. Absence of ascites at recurrence (<500 ml)

278 Ovarian Cancer - From Pathogenesis to Treatment

3. ECOG performance status ≤1 Tian Scoring System [33]

3. Progression-free interval 4. CA 125 at recurrence

6. Performance status SeC-Score [34]

1. CA 125 at recurrence 2. HE4 at recurrence 3. Presence of ascites

Minaguchi Proposal [37] 1. TFI >12 m (versus < 12 m)

1. Time to recurrence (DFI)

4. PS 0

disease).

5. Presence of ascites at recurrence

[none, 0.1–1 cm (2): >1 cm (4)]. Low and high-risk models were defined. The difference in median survival between the two groups (63.0 and 19.1 months) was highly significant, and they reported that complete surgical resection was the goal if survival gain was to be maximised. Their model, however, is arguably not straightforward. Note is made that the results of imaging had more influence on decision making (ascites and number of sites of disease) than in the AGO predictive model. In contrast, other studies have reported an improved outcome with single site versus multiple site recurrence [31] and with a DFI of 24 months or more [32].

Tian et al. [33] reported on another model in an attempt to better define those patients with recurrent disease most likely to benefit from cytoreductive surgery. Six criteria were identified initial FIGO stage, residual disease after primary cytoreduction, progression-free interval, ECOG performance status, CA125 and ascites. They categorised patients into low and high-risk groups based on the score. Compared to other models they reported lower complete cytoreduction rates (53.4% in the low risk group and 20.1% in the high-risk group) than in DESKTOP I. Another group proposed another model which they defined as the SeC-score using four criteria [34]: preoperative CA 125, pre-operative HE4, ascites and residual disease at primary surgery. They reported a sensitivity and specificity of 82 and 83%. This is one of the few reports to comment on the potential value of CA125, and in a previous study an elevated CA 125 was reported as a negative prognostic factor [35]. Angioloi et al. were the only group reporting on the newer tumour marker, HE4, and the only one in which performance status was not considered. Again in this model, as in the AGO model, the role of pre-operative imaging was essentially only to measure the volume of ascites. Frederick et al. [36] reported in a study on 62 patients with prior complete cytoreduction and platinum-sensitive disease that the only pre-operative factor predicting prolonged survival was a CA125 of less than 250 U/ml which was associated with complete surgical cytoreduction. A Japanese group proposed another model using four criteria [37]—treatment-free interval > 12 months, single site disease, absence of distant metastasis(es) and performance status of 0. Depending on the number of favourable factors, the outcome in terms of complete resection, and overall survival were significantly different.

A number of studies have assessed the two most used predictive models—that proposed by Harter (AGO) and that proposed by Tian [23, 33]. Janco et al. [38] reported that although a positive AGO score was predictive of complete SCR in 79% of patients, in 64.4% of AGO negative cases complete SCR could also be achieved—and as such the AGO score was not an independent factor associated with improved survival. Similar findings of complete cytoreduction—high positive predictive value and high false negative rates—were reported for both models in a population based study on Dutch patients [39]. In this study, 48% of patients had had chemotherapy before surgical cytoreduction but this did not impact on their results. Following on from an earlier proposal for surgical resection in ROC [40], the Memorial Sloan Kettering group compared their scoring system to the AGO and the Tian models in identifying those patients likely to benefit from secondary cytoreductive surgery—that is, those patients in whom complete surgical resection is more likely to be achieved. They proposed to offer secondary cytoreductive surgery to those with: (1) a disease-free interval of less than 6 months, if there was single site disease, (2) disease-free interval of 12–30 months, even if multiple sites of disease provided there was no carcinomatosis and (3) those with carcinomatosis, if the disease-free interval was more than 30 months. These selection criteria might be considered to be counterintuitive and are different to those of previous reports, but their assessment of the impact of carcinomatosis, is similar to that of the DESKTOP I study, albeit in the context of a longer DFI. They reported [41] that their model was more predictive of complete resection than either the AGO or Tain model. A study from two French centres [42], where initial laparoscopic assessment was common, both the AGO and Tian models were used to evaluate patients; they reported high positive predictive values for complete cytoreduction (80.6 and 74%, respectively, for each model) yet high false negative values (65.4 and 71.4%, respectively).

disease and its management (e.g. complete versus incomplete surgical cytoreduction) have a

Surgery for Recurrent Ovarian Cancer http://dx.doi.org/10.5772/intechopen.71587 281

Most recently the preliminary results of one of the RCTs on secondary cytoreductive surgery for recurrent ovarian cancer, DESKTOP III, have been reported in an abstract at the 2017 meeting of ASCO [49]. These were that (1) complete resection was achieved in 67% of patients, (2) there was an increase in PFI (14 months versus 19.6 months), (3) an increase in time to first subsequent treatment (TFST) (13.9 months and 21 months) and (4) data on OS are

There are now numerous reports on secondary cytoreductive surgery (SCS) for recurrent ovarian cancer, with the focus on the epithelial subtype. They consistently show a benefit in overall survival—that is in ROC, complete surgical cytoreduction (with or without subsequent chemotherapy) is superior to chemotherapy only in these patients. The counter-argument is that the cases selected for surgery have more favourable features than those treated with chemotherapy alone. But as with primary disease, there is a subgroup who will not undergo surgery and be treated with chemotherapy alone, or rarely palliative care only. These treatment options should not be seen as competing for patients or as an either/or dilemma but as part of the multi-disciplinary team decision as to what is the best management for a particular patient. The initial report by Berek et al. [50] on ROC showed a survival benefit where the surgical result was optimal (<1.5 cm residual) compared to suboptimal. In a later small study on 36 patients Eisenkop, and a subsequent study by the same authors on 106 patients [43, 44] reported a survival benefit from cytoreduction which was compromised by prior second-line chemotherapy before secondary cytoreductive surgery and where the tumour burden (maximum tumour diameter) was large (>10 cm). Their reports are unusual in that most other reports do not consider either factor as important in case selection for SCS. They also reported that the key surgical factor improving overall survival was complete cytoreduction. Other reports have found the same association and reported [51] that chemotherapy before surgical cytoreduction

A common intraoperative finding in recurrent disease is carcinomatosis, which is most problematic where there is extensive involvement of the small bowel serosa and/or mesentery and often results in incomplete surgical cytoreduction. However, the DESKTOP I and II trials reported that even with carcinomatosis, if complete surgical clearance is achieved, carcinomatosis is not a negative prognostic factor in recurrent disease. Indeed, Chi et al. also consider that carcinomatosis is not a contra-indication to secondary cytoreductive surgery if the diseasefree interval is 30 months or more as there is patient benefit if CSC is achieved [40, 41]. In a retrospective review of patients with ROC treated in the CALYPSO trial [52], complete surgical cytoreduction was associated with improved survival compared to patients treated with chemotherapy alone; however, as patients who had less favourable features and who did not have complete cytoreduction derived notably less benefit from surgery, then, as noted by the authors,

major impact on the surgical decision making for recurrent disease.

5. SCS in platinum-sensitive recurrent ovarian cancer

immature.

had a negative impact on surgery.

It can been seen than that although various models have been proposed with some common criteria, the more commonly used AGO and Tian models are associated with significant false negative predictions. It is of no surprise that the factors associated with improved survival in ROC and factors associated with increased rate of CSC in ROC, are similar (Tables 1 and 3). Perhaps surprising is that in most series pre-operative CA125 is not considered relevant. Most studies do not report on or recommend an initial laparoscopic assessment, a procedure not without risks, limitations and the associated logistic problems of planning operating lists. Other than Eisenkop's early reports [43, 44], it is also surprising that in most other later models determining and evaluating criteria for surgery of ROC, tumour volume or size of recurrence were not considered relevant. An exception is the report by Onda et al. [45] in which size of recurrent disease or tumour burden was an important factor in case selection. While much emphasis has been given to the importance of complete resection in primary EOC and the positive impact on survival, some reports have emphasised that initial tumour burden in primary disease limits the gains from such surgery—the argument again about surgical skill and tumour biology [46–48]. If indeed tumour burden is important in primary disease, arguably it should be of similar if not more importance in recurrent disease, where chemotherapy is less effective. Furthermore, it is quite clear that patients treated for primary EOC by gynaecological oncologists who achieve CSC have an improved outcome when the cancer recurs, compared to patients in whom primary surgery was incomplete. The positive effects of optimum treatment of primary EOC, continue through recurrent disease. Quite evidently, the characteristics of primary

disease and its management (e.g. complete versus incomplete surgical cytoreduction) have a major impact on the surgical decision making for recurrent disease.

Most recently the preliminary results of one of the RCTs on secondary cytoreductive surgery for recurrent ovarian cancer, DESKTOP III, have been reported in an abstract at the 2017 meeting of ASCO [49]. These were that (1) complete resection was achieved in 67% of patients, (2) there was an increase in PFI (14 months versus 19.6 months), (3) an increase in time to first subsequent treatment (TFST) (13.9 months and 21 months) and (4) data on OS are immature.
