The importance of surgical staging

The importance of optimal surgical staging is underscored by the results in the Adjuvant Chemotherapy in Ovarian Neoplasms (ACTION) study . The study randomised women with early-stage ovarian cancer to platinum-based chemotherapy or observation and found a recurrence-free survival (RFS) benefit in favour of adjuvant chemotherapy (70% vs 62%, HR 0.64, 95% CI 0.46–0.89), with no difference in cancer-specific survival (CSS). However, despite recommendations regarding surgical staging in the study protocol, only one-third of the patients in this study underwent optimal surgical staging . Sub-group analyses demonstrated that the benefits of chemotherapy were confined to women with sub-optimal surgical staging (RFS, 65% vs 56%, HR 0.60, 95% CI 0.41–0.87; CSS, 80% vs 69%, HR 0.58, 95% CI 0.35–0.95), with no significant improvement in either RFS or CSS in optimally staged women , suggesting that the benefits seen with adjuvant chemotherapy reflect treatment benefit in those patients with unrecognised and more advanced stage disease. Although this may be correct, this finding was based on a sub-group analysis, and the omission of chemotherapy in optimally staged women with early-stage ovarian cancer and high-risk features was not supported by randomised evidence.

Selection of chemotherapy

Platinum-based chemotherapy is recommended for the treatment of early-stage ovarian cancer; however, the key studies of chemotherapy in women with early-stage ovarian cancer have largely used older regimens (for example, the most commonly used regimen in the ACTION study was cisplatin and cyclophosphamide), which have been superseded by less toxic alternatives. Carboplatin (AUC = 5–6) and paclitaxel (175 mg/m ² ) administered once every three weeks is a commonly used regimen depending on its activity in advanced-stage ovarian cancer and a more favourable toxicity profile . This is supported by the results of randomised trials in advanced disease demonstrating that the combination of cisplatin and paclitaxel is superior to cisplatin and cyclophosphamide and the improved therapeutic index of carboplatin compared to cisplatin .

Common acute toxicities associated with carboplatin and paclitaxel include fatigue, nausea, alopecia, myalgia, myelosuppression and hypersensitivity reactions. Chemotherapy-induced peripheral neuropathy occurs in up to 73% of patients receiving paclitaxel (all grades) . Neuropathy deserves special note because in contrast to other acute toxicities, it can take many months to show clinical improvement following treatment cessation, and residual neuropathy following treatment may be permanent. Patients should be closely monitored during treatment, and dose reduction or cessation is required in patients who develop significant neuropathy. At present, there are no strategies to predict or prevent neurotoxicity, and consideration should be given to avoid the use of paclitaxel in patients with pre-existing neuropathy and substitute docetaxel for paclitaxel .

Duration of treatment and histological sub-types

The Gynecologic Oncology Group (GOG) reported a randomised controlled trial of three versus six cycles of adjuvant carboplatin (AUC = 7.5) and paclitaxel (175 mg/m ² ) administered every three weeks in women with high-risk, early-stage ovarian cancer . This study found that longer treatment was associated with a 24% reduction in recurrence risk (HR 0.76; 95% CI 0.51–1.13); however, this did not reach statistical significance (p = 0.18) and came at a cost of additional toxicity. A subsequent exploratory analysis found that longer adjuvant therapy was associated with a significant reduction in recurrence risk for high-grade serous tumours (HR 0.33, 95% CI 0.14–0.77; p = 0.04) but not non-serous tumours (HR 0.94, 95% CI 0.60–1.49) . There was no benefit for longer adjuvant therapy in any other sub-group of interest, including age, performance status, stage, grade, presence of ascites, tumour rupture, and positive cytology. On this basis, women with high-risk early-stage grade 3 serous ovarian cancer should receive six cycles of adjuvant chemotherapy, but a shorter duration may be sufficient for patients with tumours having non-serous histology.

Patients with clear cell histology also warrant special consideration. These tumours have traditionally been included in “high-risk” categories of women with early stage ovarian cancer and offered chemotherapy, however, they have a much lower rate of response to chemotherapy. Moreover, the absolute benefit of adjuvant chemotherapy has been questioned as the survival rate in patients with surgical stage IA clear cell cancer is greater than 95% . However, the NCCN 2016 guidelines still recommend adjuvant chemotherapy in all patients with stage I clear cell cancer, and this remains a controversial issue . It is beyond the scope of this chapter to discuss radiation, but a large retrospective study from Canada suggested that radiotherapy in combination with chemotherapy appeared to be associated with better outcomes in a subset of patients with stage IC and stage II clear cell ovarian cancer with a 20% increase in 5-year disease-free survival .

The importance of surgical staging

The importance of optimal surgical staging is underscored by the results in the Adjuvant Chemotherapy in Ovarian Neoplasms (ACTION) study . The study randomised women with early-stage ovarian cancer to platinum-based chemotherapy or observation and found a recurrence-free survival (RFS) benefit in favour of adjuvant chemotherapy (70% vs 62%, HR 0.64, 95% CI 0.46–0.89), with no difference in cancer-specific survival (CSS). However, despite recommendations regarding surgical staging in the study protocol, only one-third of the patients in this study underwent optimal surgical staging . Sub-group analyses demonstrated that the benefits of chemotherapy were confined to women with sub-optimal surgical staging (RFS, 65% vs 56%, HR 0.60, 95% CI 0.41–0.87; CSS, 80% vs 69%, HR 0.58, 95% CI 0.35–0.95), with no significant improvement in either RFS or CSS in optimally staged women , suggesting that the benefits seen with adjuvant chemotherapy reflect treatment benefit in those patients with unrecognised and more advanced stage disease. Although this may be correct, this finding was based on a sub-group analysis, and the omission of chemotherapy in optimally staged women with early-stage ovarian cancer and high-risk features was not supported by randomised evidence.

Selection of chemotherapy

Platinum-based chemotherapy is recommended for the treatment of early-stage ovarian cancer; however, the key studies of chemotherapy in women with early-stage ovarian cancer have largely used older regimens (for example, the most commonly used regimen in the ACTION study was cisplatin and cyclophosphamide), which have been superseded by less toxic alternatives. Carboplatin (AUC = 5–6) and paclitaxel (175 mg/m ² ) administered once every three weeks is a commonly used regimen depending on its activity in advanced-stage ovarian cancer and a more favourable toxicity profile . This is supported by the results of randomised trials in advanced disease demonstrating that the combination of cisplatin and paclitaxel is superior to cisplatin and cyclophosphamide and the improved therapeutic index of carboplatin compared to cisplatin .

Common acute toxicities associated with carboplatin and paclitaxel include fatigue, nausea, alopecia, myalgia, myelosuppression and hypersensitivity reactions. Chemotherapy-induced peripheral neuropathy occurs in up to 73% of patients receiving paclitaxel (all grades) . Neuropathy deserves special note because in contrast to other acute toxicities, it can take many months to show clinical improvement following treatment cessation, and residual neuropathy following treatment may be permanent. Patients should be closely monitored during treatment, and dose reduction or cessation is required in patients who develop significant neuropathy. At present, there are no strategies to predict or prevent neurotoxicity, and consideration should be given to avoid the use of paclitaxel in patients with pre-existing neuropathy and substitute docetaxel for paclitaxel .

Duration of treatment and histological sub-types

The Gynecologic Oncology Group (GOG) reported a randomised controlled trial of three versus six cycles of adjuvant carboplatin (AUC = 7.5) and paclitaxel (175 mg/m ² ) administered every three weeks in women with high-risk, early-stage ovarian cancer . This study found that longer treatment was associated with a 24% reduction in recurrence risk (HR 0.76; 95% CI 0.51–1.13); however, this did not reach statistical significance (p = 0.18) and came at a cost of additional toxicity. A subsequent exploratory analysis found that longer adjuvant therapy was associated with a significant reduction in recurrence risk for high-grade serous tumours (HR 0.33, 95% CI 0.14–0.77; p = 0.04) but not non-serous tumours (HR 0.94, 95% CI 0.60–1.49) . There was no benefit for longer adjuvant therapy in any other sub-group of interest, including age, performance status, stage, grade, presence of ascites, tumour rupture, and positive cytology. On this basis, women with high-risk early-stage grade 3 serous ovarian cancer should receive six cycles of adjuvant chemotherapy, but a shorter duration may be sufficient for patients with tumours having non-serous histology.

Patients with clear cell histology also warrant special consideration. These tumours have traditionally been included in “high-risk” categories of women with early stage ovarian cancer and offered chemotherapy, however, they have a much lower rate of response to chemotherapy. Moreover, the absolute benefit of adjuvant chemotherapy has been questioned as the survival rate in patients with surgical stage IA clear cell cancer is greater than 95% . However, the NCCN 2016 guidelines still recommend adjuvant chemotherapy in all patients with stage I clear cell cancer, and this remains a controversial issue . It is beyond the scope of this chapter to discuss radiation, but a large retrospective study from Canada suggested that radiotherapy in combination with chemotherapy appeared to be associated with better outcomes in a subset of patients with stage IC and stage II clear cell ovarian cancer with a 20% increase in 5-year disease-free survival .

Scheduling of intravenous chemotherapy

Carboplatin/paclitaxel combination has traditionally been administered once every 3 weeks at doses of AUC = 5–6 and 175 mg/m ² , respectively. There is emerging evidence that delivery of one or both agents in a weekly schedule (‘dose-dense’ therapy) is associated with equivalent or improved outcomes and a different toxicity profile to the conventional approach. The JGOG 3016 study randomised 631 Japanese women with stages II–IV EOC to carboplatin AUC = 6 and paclitaxel 175 mg/m ² administered once every 3 weeks or carboplatin AUC = 6 administered every 3 weeks combined with weekly paclitaxel 80 mg/m ² for six cycles. At a median follow-up of 77 months, the dose-dense arm was found to be associated with superior PFS (median 28 vs 17.5 months) and OS (100.5 vs 62 months) . The benefits of dose-dense therapy were greatest in women with sub-optimally cytoreduced disease, and scheduling did not appear to make a difference in outcomes for women with clear cell or mucinous cancers on sub-group analysis. It should be noted that in this study, dose-dense therapy was associated with significantly higher rates of treatment discontinuation (52% vs 37%) or delays (76% vs 67%) due to toxicity, largely haematological.

GOG 262 attempted to validate these findings in a western population . However, there were notable differences as bevacizumab administration was permitted at the discretion of clinicians and was given to 84% of the patients. At a median follow-up of 28 months, no differences were seen between the two chemotherapy treatment arms in PFS for the overall study population (14 vs 15 months). However, among patients who did not receive bevacizumab, dose-dense therapy was associated with superior PFS (14 vs 10 months), which is in agreement with the outcomes of the JGOG 3016 study. Difference in PFS was not noted in women who received bevacizumab. These findings should be interpreted with caution because of the relatively small number of patients who did not receive bevacizumab and the non-randomised nature of this comparison. A broader discussion of the role of bevacizumab and other targeted therapies in the management of ovarian cancer is covered elsewhere in this edition.

A third approach to the delivery of dose-dense intravenous (IV) therapy was explored in the MITO 7 study, which randomised women with stage IC–IV EOC to a standard three weekly carboplatin and paclitaxel regimen or a regimen where both carboplatin and paclitaxel were delivered in a low dose once every week (doses AUC = 2 and 60 mg/m ² , respectively) . No differences in PFS or OS were noted with the dose-dense approach in this study, although there were notable differences in the toxicity and quality of life (QOL) outcomes between the arms. The conventional therapy arm was associated with a cyclical deterioration in QOL scores following each dose of chemotherapy, whereas the weekly therapy arm was associated with a transient detriment after the first treatment and stable QOL scores thereafter. There was also less grade 3/4 myelosuppression and neuropathy observed with the weekly regimen.

The ongoing ICON 8 randomised study has closed recruitment and will attempt to compare all three of these approaches to carboplatin and paclitaxel scheduling . In the interim, a dose-dense regimen in keeping with the JGOG study may be considered an active alternative regimen for women with non-mucinous or clear cell cancers, particularly those who will not receive bevacizumab. In addition, the low-dose weekly regimen used in the MITO 7 study is a reasonable option for women deemed likely to have poor tolerance to conventional schedules because of their performance status or comorbidities.

Intraperitoneal chemotherapy

The direct delivery of chemotherapy into the peritoneal cavity is a theoretically attractive and biologically plausible means of delivery of high concentration of active drugs to the most likely sites of disease recurrence in advanced ovarian cancer. Platinum/taxane combination therapy may be delivered through the intraperitoneal (IP) route in patients with good performance status who have optimally cytoreduced disease. IP chemotherapy is not a suitable option for women with sub-optimally de-bulked disease as the surface penetration of IP chemotherapy directly into tumours is limited to 1–2 mm.

IP chemotherapy is typically administered in the context of a combination of IV and IP therapy such as that utilised in the GOG 172 study, where patients received IV paclitaxel 135 mg/m ² and IP cisplatin 100 mg/m ² in week 1 and IP paclitaxel 60 mg/m ² in week 2 of a three weekly cycle of treatment . Several randomised trials and a Cochrane meta-analysis demonstrated superior outcomes with this approach compared to conventional chemotherapy . The meta-analysis included nine studies in 2119 women and showed that compared to IV therapy, IV/IP therapy was associated with improved disease-free survival (HR 0.78, 95% CI 0.70–0.86) and OS (HR 0.81, 95% CI 0.72–0.90) .

IP chemotherapy can be associated with considerable toxicity, with higher rates of neurotoxicity, abdominal discomfort and poorer self-reported QOL . A significant proportion of women enrolled in these studies were unable to complete the treatment through the IP route because of toxicity or IP catheter-related complications (for example, in GOG 172, 42% patients completed all planned cycles of IV/IP therapy compared to 83% for IV chemotherapy). IP catheter-related complications occur in up to one-third of the patients, most commonly catheter blockage and infection but also including more serious complications such as catheter erosion into abdominal structures .

It should be noted that most of the investigational arms in the studies of IP therapy involve changes to conventional regimens other than the simple substitution of IV with IP chemotherapy, including the addition of doses of chemotherapy beyond day 1 of the three weekly treatment cycle. This has led some to question whether the apparent benefit of IP treatment approaches represents chemotherapy dose intensity rather than a superior route of administration. This is the subject of ongoing investigation, including the GOG 252 study. Preliminary results from this study suggest that dose-dense IV carboplatin and paclitaxel were associated with a similar PFS to IV/IP therapy (27 vs 28 months), with more neurotoxicity, abdominal pain and worse QOL in the IP therapy arm . Both arms also received bevacizumab in this study.

Neo-adjuvant chemotherapy

Neo-adjuvant chemotherapy (NACT) is typically considered for patients who are not good candidates for surgery at the time of diagnosis because of the extent of disease, poor performance status or medical comorbidities. Most patients receive three cycles of chemotherapy, and provided there is evidence of response, they are offered interval de-bulking surgery followed by additional three cycles of chemotherapy. This approach has been supported by two randomised trials, namely the EORTC 55971 and CHORUS studies, both of which found no difference in PFS or OS in both the arms but less morbidity associated with NACT . However, both trials have been criticised because the median OS, mean operative time and rates of optimal cytoreduction were low. The choice between primary cytoreductive surgery (PCS) and NACT remains controversial. However, the rate of NACT has significantly increased from 16% to 34% over the last decade in NCI-designated cancer centres in patients with stage IIIC EOC and up to 62% in patients with stage IV EOC .

The American Society of Clinical Oncology and the Society of Gynecologic Oncology recently released a position paper on the use of NACT in advanced ovarian cancer . The consensus panel concluded that NACT is the preferred treatment option for women with advanced ovarian cancer if it is unlikely that PCS can reduce the disease to <1 cm, provided that the patient has been assessed by a gynaecologic oncologist. However, PCS is recommended over NACT in women with a high likelihood of achieving cytoreduction to <1 cm, ideally to no visible disease, and who are fit for surgery. In addition, the joint position paper suggested that NACT is an alternative to up-front surgery for women with potentially resectable disease who prefer the neo-adjuvant approach as chemotherapy has not been found to be inferior to surgery in terms of PFS or OS in this patient group; this is likely to be more contentious as the randomised trials included a subset of patients with adverse prognostic features at presentation.

Histology and treatment selection

High-grade serous EOC is generally very sensitive to platinum-based chemotherapy, with response rates of 80% or more. In contrast, clear cell carcinomas have poor response rates to platinum-based chemotherapy, with reports that up to 52% will progress on first-line therapy, and show response rates ranging from 45% to as low as 11% . A large international phase III study recruited 667 patients with stages I–IV clear cell ovarian cancer and compared cisplatin/irinotecan with paclitaxel/carboplatin as adjuvant chemotherapy (GCIG/JGOG3017). The results were recently reported and showed that 2-year PFS rates were no different and approximately 75%. Almost 65% of the patients had stage I disease and had an 89% 2-year PFS compared to a 40%–50% 2-year PFS in stages II–IV . Strategies targeting biological pathways unique to clear cell cancers are the subject of investigation ; however, at present, there is no alternative standard of care to platinum-based chemotherapy for advanced clear cell cancers.

Mucinous tumours also have a very poor response rate of ≤23%, and up to 63% of the patients show tumour progression on platinum based-chemotherapy . As these tumours have histopathological similarities to gastrointestinal tumours, approaches utilising chemotherapy regimens conventionally used for colorectal cancer have been used, e.g. fluoropyrimidines in combination with oxaliplatin. However, a randomised phase II trial designed to compare a conventional ovarian cancer regimen of carboplatin/paclitaxel to capecitabine/oxaliplatin as first-line therapy for mucinous ovarian cancers was closed early because of poor recruitment. Notably, after central pathology review, the majority of cases enrolled were not found to be primary ovarian cancers but rather metastatic mucinous cancers from other sites . This underscores the need for a thorough work-up of apparent ‘ovarian’ mucinous tumours to exclude a gastrointestinal primary.

Low-grade serous tumours are biologically distinct from high-grade serous cancers and should be considered separately. These tumours are typically indolent and slow-growing tumours and have very low response rates to chemotherapy . Maximal cytoreductive surgery is the mainstay of their management, whereas strategies targeting pathways such as MEK and KRAS/BRAF remain under investigation.

Maintenance therapy

The majority of women will respond to initial therapy for advanced stage EOC; however, the disease will subsequently recur in 80%–85% of the patients. Maintenance chemotherapy has been investigated, although present data do not support such approaches. Moreover, a Cochrane meta-analysis of eight trials demonstrated no significant improvements in OS to justify the additional toxicity associated with protracted treatment . Maintenance strategies involving targeted therapies such as angiogenesis inhibitors may play a role ; these will be discussed elsewhere.