3. Determination of recurrent ovarian cancer

Recurrence is documented clinically, and/or by tumour marker levels and/or radiologically and in different clinical units the policy of post-treatment surveillance is variable. The clinical determination of relapse may be in an asymptomatic or symptomatic patient, and rarely OC patients may present acutely, for example, with bowel obstruction. Indeed, previously treated OC patients who develop bowel obstruction almost always have (recurrent) disease as the cause, even if this is not suspected on tumour marker levels or on imaging.

#### 3.1. Clinical features

primary or subsequent treatments. Frequently these develop together and herald relentless progression until the patient succumbs to disease. For all cancers, these processes show a greater propensity with higher stage (or TNM) of disease at presentation. Furthermore, it is known that certain types or subtypes of a given cancer have a greater or lesser tendency to

The typical clinical picture of ovarian cancer (OC) is presentation with advanced stage disease in the post menopausal woman and despite advances in medical and surgical treatments, most patients will die of disease. While arguably the goal of primary treatment is cure, this applies to those with early stage disease but not for all subtypes. Data from CRUK [1] show that there were 7378 new cases of OC and 4128 deaths from OC in 2014. These deaths were in most cases due to recurrent disease rather than primary disease. Survival is also associated with lower patient age and the overall 5-year survival is about 35%; the 5-year survival for stages III and IV disease is about 20 and <5%, respectively [1]. The majority of data on ovarian cancer is based on epithelial ovarian cancer (EOC) and this review predominantly deals with recurrent EOC.

This is the detection of the cancer following a period of time after completion of primary treatment. The NCI Dictionary of Cancer terms [2], defines recurrent cancer as "Cancer that has recurred (come back) after a period of time during which the cancer could not be detected". This is vague and open to interpretation and in clinical practice requires more careful scrutiny: 1. How undetectable disease is defined at the end of primary treatment and how recurrence

2. How the recurrent disease is detected—clinically, by tumour marker(s), radiologically?

3. The time intervals in the follow-up of patients, the methods of surveillance and how often

4. Whether there is a clear distinction between persistence of disease following primary

For example, a unit that regularly scans patients after primary treatment may detect evidence of recurrent disease sooner than a unit which relies on serial tumour markers. Indeed, 2 units may use imaging as part of surveillance but one unit may scan more often that another, or measure tumour markers more frequently than another. Complicating this further is that not all recurrences are associated with rising tumour markers and different modalities of imaging have differing sensitivities and specificities in detecting early or small volume recurrent disease. Compounding the understanding of the role of, and efficacy of, different managements for recurrent disease is tumour and patient heterogeneity [3]. As a consequence, caution needs to be given to the interpretation of data on the efficacy of different managements of recurrent cancer —including the role of surgery in recurrent ovarian cancer (ROC). Trial design and the endpoints of trials have important implications [3–5]. It is generally accepted though that overall survival (OS) is the most clinically relevant and the most clearly definable endpoint [3]. Modern imaging and tumour makers have replaced what was the common practice of second look laparotomy

metastasise and recur than others.

272 Ovarian Cancer - From Pathogenesis to Treatment

2. Defining recurrent cancer

is defined?

these are used.

treatment and recurrence.

Recurrence may be suspected from the patient's history—symptoms include weight loss, weight gain (e.g. from ascites), leg swelling (unilateral or bilateral), dyspnoea, pelvic pressure symptoms and loss of appetite. More unusual symptoms relate to the paraneoplastic syndrome including features associated with hypercalcaemia, myositis, erythema nodosum and herpes zoster. Less commonly patients have haematuria, vaginal or rectal bleeding. The patient may of course be asymptomatic.

The clinical examination, which should include assessment of the lymph nodes, abdominal and pelvic examination and recto-vaginal examination, may be normal. If the patient presents more acutely, for example with dyspnoea or evidence of bowel obstruction, there are usually concerning clinical findings.

#### 3.2. Blood results

Unless clinically indicated, the usual test off treatment is to measure the serum tumour marker(s). The evidence that this is useful clinically and contributes to more efficacious treatment and 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 unequivocally endorsed routine post-treatment surveillance using serum tumour marker(s).

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

Surgery for Recurrent Ovarian Cancer http://dx.doi.org/10.5772/intechopen.71587 275

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

1. Recurrent ovarian cancer with pelvic and/or abdominal disease (including retroperitoneal

2. Surgery and intraperitoneal chemotherapy (IP) or heated intraperitoneal chemotherapy

5. Further recurrence in patients previously operated on or treated for recurrence.

6. Recurrent non-epithelial ovarian cancer (borderline tumours are discussed elsewhere).

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

a. DESKTOP III Trial: This follows on from the DESKTOP I and II trials and again the predictive model is the positive AGO score for complete secondary surgical cytoreduction. In this trial, two groups are compared—chemotherapy only group and cytoreductive surgery

b. SOCceR Trial: This Dutch trial is of secondary CRS and chemotherapy compared to

c. GOG 213 Trial: In this trial after randomisation to cytoreductive surgery (CRS) patients are then randomised to one of four treatment arms, two of which contain bevacizumab.

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

chemotherapy alone in recurrent disease. The primary endpoint is PFI.

lymph nodes); the patient may asymptomatic or symptomatic.

3. Recurrent ovarian cancer outside the pelvis and abdomen.

4. Recurrent ovarian cancer and bowel obstruction.

which can be completely resected.

Broadly these may be described as:

(HIPEC) for recurrent cancer.

platinum-sensitive EOC [16–18].

followed by chemotherapy group.

be considered.

#### 3.3. Imaging

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 in the management decisions.

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 rather than reliance on a brief summary in patient correspondence.
