5.1 Introduction

Ovarian cancer is a chemosensitive disease, and the use of immediate first line platinum-based chemotherapy improves the prognosis for patients with advanced disease. Although most women with ovarian cancer will have some response to chemotherapy, the likelihood of relapse is high.⁹³ Twenty five years of clinical research have defined the role of existing chemotherapeutic agents in the first line management of advanced ovarian cancer.

5.2 Timing of chemotherapy

One observational study indicates that the interval from primary surgery to chemotherapy is not an independent prognostic factor for progression-free survival.⁹⁴ Consensus of the epithelial ovarian cancer guideline development group is that chemotherapy should be started no later than eight weeks after surgery. Evidence level 3

Chemotherapy should be started no later than eight weeks after surgery.

5.3 Early stage disease

Adjuvant systemic treatment of early stage (FIGO stage I) ovarian cancer remains a controversial area. The National Institutes of Health (NIH) guideline recommends carboplatin chemotherapy for patients with early stage disease and additional risk factors, to reduce the risk of disease recurrence and ensuing risk of death.⁹⁵ Additional risk is conferred by the presence of moderate or poorly differentiated tumours, stage Ic disease including surgical rupture, and clear cell histological subtype.⁹⁶ Evidence level 4,2+

Two RCTs demonstrate the role of adjuvant chemotherapy for early stage epithelial cancer patients.^{75, 76} The ICON 1 trial found a significant reduction (9%) in odds of death and an improvement in recurrence-free survival (11%) for early stage epithelial cancer patients following the use of adjuvant chemotherapy compared with observation following surgery.⁷⁶ The ACTION trial found no difference in overall survival but disease-free survival was significantly improved in women who had undergone non-optimal surgical staging (8%).⁷⁵ In the ACTION study one third of patients were optimally staged whereas in the ICON study the majority of patients were not optimally staged. Analysis of combined data from these studies demonstrated that platinum-based adjuvant chemotherapy improved overall survival by 8% and recurrence-free survival by 11% at five years.⁷⁷ Evidence level 1+

Carboplatin can be offered to all early stage epithelial ovarian cancer patients.

Chemotherapy for patients with disease confined to the ovaries where the tumour is welldifferentiated (FIGO stage 1a grade 1 and FIGO stage 1b grade 1, see Annexes 1 and 2), may be deferred if optimal surgery has been performed.

5.4 Neoadjuvant chemotherapy

There is debate about the precise sequence in which surgery and chemotherapy should be used in a woman with advanced disease. The usual approach is to operate first. No evidence from RCTs could be identified on the role of neoadjuvant chemotherapy. Descriptive studies demonstrate that in advanced disease chemotherapy can be offered as a first treatment option where there is no doubt about the diagnosis.^{97, 98} In advanced disease neoadjuvant chemotherapy and delayed primary surgery or primary surgery followed by chemotherapy are currently being compared in a European Organisation for Research and Treatment of Cancer (EORTC) RCT. Evidence level 3

5.5 Advanced disease

5.5.1 ROLE OF PLATINUM AGENTS

Meta-analyses show significant benefit for use of platinum.^{99, 100} Evidence level 1++

First line chemotherapy treatment of epithelial ovarian cancer should include a platinum agent either in combination or as a single agent, unless specifically contraindicated.

5.5.2 CHOICE OF PLATINUM AGENTS

The platinum-based drugs cisplatin and carboplatin are equally efficacious in the treatment of epithelial ovarian cancer.⁹⁹ Carboplatin has a more favourable toxicity profile and, as it can be delivered as an outpatient regimen, is simpler to administer than cisplatin. The combination of carboplatin and paclitaxel is as efficacious as cisplatin and paclitaxel combination therapy.¹⁰¹ Evidence level 1++

Carboplatin is the platinum drug of choice in both single and combination therapy.

5.5.3 TAXANES

Two high quality RCTs support the use of paclitaxel and cisplatin as an efficacious combination for advanced ovarian cancer.^{102, 103} As these trials were limited to surgically managed patients who were fit enough to meet the entrance criteria for clinical trials, the general applicability of taxanes remains in question. The use of taxane combination therapy is widespread throughout Scotland and has been recommended by NICE and NHS Quality Improvement Scotland.¹⁰⁴ A further study has suggested that carboplatin can be substituted for cisplatin.¹⁰¹ Evidence level 1++

Although one RCT has shown that single agent cisplatin yielded both equivalent response rates and equivalent overall survival to cisplatin and paclitaxel, this trial is difficult to interpret due to treatment crossover issues.¹⁰² The study recommends the taxane combination on the grounds of reduced toxicity compared to single agent cisplatin. The ICON 3 trial demonstrates equal effectiveness for carboplatin or CAP (the combination regimen containing cyclophosphamide, doxorubicin and cisplatin) compared with paclitaxel and carboplatin in ovarian cancer.¹⁰⁵ ICON 3 does not imply that paclitaxel has no role in the treatment of ovarian cancer, but it does suggest that the dramatic difference seen in the earlier studies was principally due to the inferiority of the cyclophosphamide and cisplatin control arm. An interpretation of a meta-analysis of all these studies does suggest a slight benefit for the taxane and platinum combination.¹⁰⁵ Evidence level 1+,1++

Paclitaxel is recommended in combination therapy with platinum in the first line post-surgery treatment of epithelial ovarian cancer where the potential benefits justify the toxicity of the therapy.

Patients who choose less toxic therapy or who are unfit for taxanes should be offered single agent carboplatin.

Where carboplatin is used as a single agent in first line therapy attention should be paid to platinum dose optimisation.

5.5.4 CYCLOPHOSPHAMIDE

The combination of platinum and cyclophosphamide has been shown to be inferior to platinum and taxane in two RCTs.^{103, 106} The use of cyclophosphamide offers no clinical benefit over other currently used cytotoxic agents in the treatment of ovarian cancer. Evidence level 1++

Cyclophosphamide is not recommended in the first line chemotherapy treatment of epithelial ovarian cancer.

5.5.5 THE ROLE OF ANTHRACYCLINES

The addition of doxorubicin to cisplatin and cyclophosphamide provides a small but significant survival advantage.¹⁰⁷ The ICON 2 study showed that single agent carboplatin was as effective as the combination regimen containing cyclophosphamide, doxorubicin and cisplatin (CAP).¹⁰⁰ Meta-analysis has shown the CAP regimen to be marginally superior to cisplatin and cyclophosphamide.¹⁰⁰ Evidence level 1+

The role of anthracyclines in first line treatment is unclear. They may be of benefit if incorporated into first line treatment, but further research is required.

The use of anthracyclines in first line chemotherapy treatment of epithelial ovarian cancer is not recommended outside RCTs.

5.6 Relapsed disease

5.6.1 SYSTEMIC THERAPY IN RECURRENT OVARIAN CANCER

The impact of chemotherapy on survival is marginal for patients with relapsed disease, particularly those with platinum-resistant relapse. As the palliative effect of chemotherapy for recurrent disease has not been tested in an RCT against best supportive care, the magnitude of effect attributable to chemotherapy in this setting is unknown.

A prospective study has demonstrated that patients whose ovarian cancer recurs more than six months after the last cycle of chemotherapy (platinum sensitive) have a good chance of responding to further palliative platinum therapy.¹⁰⁸ Patients whose ovarian cancer recurs within six months after the last cycle of chemotherapy (platinum resistant) have a low chance of response to further platinum chemotherapy. Such patients achieve a 10 to 40% overall response rate to active non-platinum agents.¹⁰⁸ Evidence level 2+

One RCT has shown that patients whose ovarian cancer recurs 12 months or more after first-line platinum-based chemotherapy who are rechallenged with a platinum-based regimen achieve significant improvement (seven to nine months advantage) in median progression-free and overall survival compared with paclitaxel.¹⁰⁹ Evidence level 1+

The ICON 4 trial assigned platinum sensitive women with relapsed ovarian cancer to one of two arms: paclitaxel plus a platinum-based drug or a platinum-based drug alone. There was a 7% improvement in survival at two years for those who received the combination of paclitaxel and platinum. Median survival increased by five months.¹¹⁰ Evidence level 1+

An RCT of paclitaxel versus topotecan (a topoisomerase inhibitor) in patients with platinum treated recurrent ovarian cancer demonstrated equivalence in overall response rate and median duration of response. Topotecan demonstrated more myelotoxicity.¹¹¹ Evidence level 1+

An RCT that compared topotecan with pegylated liposomal doxorubicin (PLD) in similar cohorts of patients found equivalent response rates, progression-free survival and overall survival.¹¹² There was a significant progression-free survival and overall survival advantage for PLD in platinum-sensitive patients that did not occur for platinum-resistant patients. NICE and NHS Quality Improvement Scotland have noted the possible cost and logistical advantages of PLD over topotecan.^{113, 114} Meta-analyses of observational studies suggest that tamoxifen may produce a response in a low proportion of women with recurrent ovarian cancer.¹¹⁵ No randomised studies were identified. Symptomatic platinum-resistant recurrence (treatment free interval less than six months) is less sensitive to chemotherapy, and the optimal agents have yet to be defined. Evidence level 1+,2++

Chemotherapy for recurrent ovarian cancer should be regarded as palliative in intent and should be reserved for symptomatic recurrence of disease.

Symptomatic platinum-sensitive cancer recurrence can be treated with further platinum and paclitaxel.

Tamoxifen should be considered in patients for whom chemotherapy is not appropriate.

Patient care should be discussed within the multidisciplinary team and where possible patients should be entered into appropriate clinical trials.

The optimal agents in platinum-resistant disease have yet to be defined and treatment should be based on specialist judgement.

Cautious clinical judgement should be used when considering the use of platinum and paclitaxel in patients with symptomatic platinum-sensitive cancer recurrence after a treatment-free interval of 6-12 months.

5.6.2 ROLE OF ERYTHROPOETIN

Anaemia is common in ovarian cancer, occurring in 50-60% of patients who are receiving chemotherapy.¹¹⁶ Anaemia can be effectively treated by blood transfusion or by the use of erythropoetin. Erythropoetin can be recommended as a safe and effective alternative for patients with anaemia who cannot be transfused. There is no evidence suggesting that erythropoetin is more effective than blood transfusion.^{117, 118} The quality of life benefits offered by erythropoetin are inconsistent.¹¹⁷ Evidence level 1++

If erythropoetin is used to treat anaemia it should only be when the haemoglobin concentration is =<10 g/dL and the dose should not exceed 450 units/kg/week.

5.7 Intraperitoneal chemotherapy

Two RCTs investigating the benefits of intraperitoneal chemotherapy in maximally cytoreduced cases of ovarian cancer have been reported.^{119, 120} Both studies reported significantly better survival in the women receiving intraperitoneal therapy but design flaws in both trials mean that intraperitoneal therapy cannot yet be recommended for routine use in optimally cytoreduced cases.^{119, 120} The results of a Gynecologic Oncology Group (GOG) study evaluating intraperitoneal chemotherapy are awaited.¹²¹ Evidence level 1-

Intraperitoneal therapy should not be routinely offered outwith clinical trials.

5.8 Administration of chemotherapy

It is the responsibility of the gynaecological cancer team to ensure that chemotherapy is given according to published guidelines and national standards.^{122, 123, 124} Evidence level 4

Staff should be experienced, trained in the safe administration of chemotherapy and be involved in on going continuing professional development (CPD) and reappraisal.

Hospital based administration of chemotherapy should take place during the working day in designated areas equipped to deal with any medical emergencies.

Chemotherapy should be administered in environments that meet the standards set out in national guidance.

5.9 Impact of chemotherapy on quality of life in relapsed disease

The management of ovarian cancer is usually characterised by multiple chemotherapeutic regimens. Response rates, especially in platinum-resistant patients, may be low and the toxicity associated with treatment impacts on patients’ quality of life.¹²⁵ The large number of varying, often complex tools applied to assess quality of life means that meta-analysis of the research is not feasible.¹²⁶ One small prospective study of palliative chemotherapy and quality of life indicates that women with advanced ovarian cancer, and those receiving prolonged cycles of chemotherapy, report deterioration in their quality of life.¹²⁷ Four cohort studies report similar findings.^{125, 128, 129, 130} Women with advanced cancer are willing to tolerate reduced quality of life for minimal therapeutic benefit.^{125, 127, 128, 129, 130} Evidence level 3,2+

Women should be given accurate information on their likely response to chemotherapy, including adverse effects, so that they can make an informed decision about whether or not to proceed with treatment.

The impact of chemotherapy toxicities on patients’ quality of life must be balanced against their anticipated response to treatment.