The Obstetrician & Gynaecologist 2007;9:4:265-269
doi: 10.1576/toag.9.4.265.27357
Copyright © 2007 by the Royal College of Obstetricians and Gynaecologists.
Current practice and new developments in ovarian cancer chemotherapy
S Nasim Ali, MRCPI, Consultant Medical Oncologist1 and
Jonathan A Ledermann, BSc MD FRCP, Professor of Medical Oncology and Honorary Consultant Medical Oncologist2
1. Clatterbridge Centre for Oncology, Clatterbridge Road, Wirral CH63 4JY, UK
2. Department of Oncology, UCL Cancer Trials Centre, 90 Tottenham Court Road, London W1T 4TJ, UK Email: j.ledermann{at}ctc.ucl.ac.uk (corresponding author)
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Abstract
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Key content:- A combination of carboplatin and paclitaxel is the most commonly used treatment for advanced ovarian cancer, a chemosensitive disease with a high recurrence rate.
- Molecular targeted agents are being investigated as a novel strategy to improve the outcome of systemic therapy.
Learning objectives:
- To study the optimum timing of chemotherapy in relation to surgery and the role of intraperitoneal therapy.
- To be aware of current chemotherapy regimens used in the management of newly diagnosed and relapsed ovarian cancer and the rationale for using them.
- To understand current areas of research using novel agents in systemic therapy and different treatment strategies.
Ethical issues:
- It is important to consider the balance between benefit and side effects of treatment for women with relapsed disease.
- Patient choice is an important consideration for the selection of chemotherapy for relapsed ovarian cancer.
- Current treatment produces only a modest gain in outcome, therefore, every effort should be made to recruit women to clinical trials.
Please cite this article as: Ali SN, Ledermann JA. Current practice and new developments in ovarian cancer chemotherapy. The Obstetrician & Gynaecologist 2007;9:265–269.
Keywords chemotherapy / intraperitoneal chemotherapy / ovarian cancer / platinum agents / taxanes
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Introduction
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Ovarian cancer is the most common gynaecological cancer and the fourth most common malignancy. It accounts for 6% of female cancer deaths in the UK.1 Epithelial ovarian cancer is a very chemosensitive tumour: approximately 80% of women respond to treatment and more than half have complete clinical remission after surgery and chemotherapy. However, the majority relapse and die of their disease because of the emergence of drug resistance.2 Chemotherapy is generally administered after surgery, but it is increasingly being used as ‘neoadjuvant’ therapy before definitive surgery (Box 1).
The management of recurrent ovarian cancer is becoming increasingly important, as women often receive several lines of chemotherapy and spend a greater proportion of their illness living with relapsed disease. For these women, trying to balance the benefit of treatment with its side effects is complex. Chemotherapy also has an important role in the management of early ovarian cancer as an adjuvant treatment following surgery.
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First-line therapy
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Platinum agents
Platinum-based drugs have been used since the mid 1970s. They are the most active agents for the treatment of ovarian cancer. Women with early-stage ovarian tumours (largely stage I, confined to the ovary) have an improved survival rate with adjuvant chemotherapy.3,4 In advanced disease, platinum-based therapy improves the tumour response rate and survival (5% at 2 years and 5 years).5–7 There is no difference in efficacy between carboplatin and cisplatin, but carboplatin has fewer side effects, with less ototoxicity, neuropathy, nephrotoxicity and emetogenesis. It is the drug of choice. Optimal dosing of carboplatin is based on the glomerular filtration rate, as the intended AUC (area under the concentration-time curve) is dependent on this. A dose of AUC 5–6 is generally used, alone or in combination with other drugs. This dose usually produces low and manageable haematological toxicity and treatment is undergone every 3 weeks, usually for six cycles.
Taxanes
Taxanes form the second most important group of drugs and were introduced into the treatment of ovarian cancer in the mid 1990s. Paclitaxel is less myelosuppressive than docetaxel and is now used routinely for first-line therapy of advanced ovarian cancer in combination with carboplatin. Two large international trials – GOG (Gynecologic Oncology Group) 1118 and the OV10 Intergroup Study9 – demonstrated that a combination of cisplatin with paclitaxel was superior to cyclophosphamide with cisplatin. Further studies demonstrated that the combination of carboplatin with paclitaxel was equivalent to cisplatin with paclitaxel, but the former combination is less toxic and has become a common standard of care. However, there is still some debate about the value of first-line combination therapy, as the very large ICON 310 trial found that survival following platinum therapy, chiefly as adequately dosed carboplatin, was equivalent to that following carboplatin with paclitaxel. A decision about the use of combination therapy versus single-agent platinum therapy therefore needs to take into account issues such as the fitness of the woman to tolerate the potential toxicities of the combination and her informed choice. The response rate to combination chemotherapy is higher than to single-agent carboplatin. This has led many to prefer to use combination chemotherapy for women with extensive residual disease after surgery, as a means of more rapidly and completely controlling symptoms.
Other agents
There has been great interest in exploring the addition of a third or fourth active agent to carboplatin with paclitaxel to improve outcome. Trials have been performed with epirubicin, pegylated doxorubicin, gemcitabine or topotecan added to standard therapy. This approach has recently been examined in an international 5-arm study comparing sequential doublet therapy and triplet therapy with carboplatin–paclitaxel. However, the preliminary results of the ICON5/GOG0182 study11 involving 4500 women has not demonstrated any significant difference in progression-free survival or overall survival after adding a third agent.
Timing of surgery in advanced tumours
The timing of surgery and chemotherapy in advanced (FIGO [International Federation of Gynecology and Obstetrics] stages III and IV) tumours is debatable. Maximal surgical debulking is associated with a better prognosis. Suboptimal surgery followed by chemotherapy and further ‘interval debulking surgery’ has been shown to have a better outcome than one suboptimal debulking operation and chemotherapy. This has raised the question of whether chemotherapy might best be employed early in the treatment of the disease so that surgery is carried out later, when the tumours are smaller and more easily resected. It is unclear whether this ‘neoadjuvant’ approach to chemotherapy is equivalent or superior to the standard approach of immediate surgery and chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial and the National Cancer Research Institute (NCRI) CHORUS studies are addressing this question.
For many women, better preoperative imaging has identified disease that is difficult to resect fully at diagnosis. Furthermore, many of these women are unwell at diagnosis and surgical morbidity would be high. Rather than subjecting women to two operations, many surgeons and oncologists advise ‘neoadjuvant’ chemotherapy followed by interval debulking surgery and the completion of chemotherapy. However, there is no evidence to support this approach.
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Relapsed disease
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Women are routinely followed up by clinical examination and measurement of CA125, a serum tumour marker that is raised in more than 85% of cases. Decisions about further treatment are usually made on the basis of clinical and or radiological relapse, rather than on raised CA125 alone. Serological relapse occurs with an average lead time of 3 months. The choice of treatment at relapse is usually based on the length of time the woman has been off treatment. Empirical observations have shown that the ‘platinum-free’ interval is a useful indicator of the probability of response to re-challenge with platinum. Women who have progressive disease on platinum therapy, or who have ceased to respond to therapy, are considered ‘platinum-refractory’, whereas those relapsing within 6 months of completing treatment are defined as ‘platinum-resistant’. Tumours relapsing 12 months or more after initial platinum therapy are considered ‘platinum-sensitive’ and those relapsing between 6 and 12 months as ‘partially platinum-sensitive’.
Platinum-sensitive ovarian cancer
Women with platinum-sensitive tumours are treated again with carboplatin or with cisplatin if they have developed carboplatin allergy after prolonged therapy. Carboplatin is now often combined with paclitaxel, following publication of the ICON 4 trial12 showing that the progression-free and overall survival rates were significantly prolonged in those randomised to platinum-based therapy and paclitaxel. However, this benefit has to be balanced against some increase in toxicity with combination therapy and women with persistent neuropathy after first-line therapy are unable to receive this combination on relapse.
A randomised trial13 of a carboplatin–gemcitabine combination compared with carboplatin also showed a benefit in progression-free, but not in overall, survival rates for combination therapy. There is also an ongoing international trial, CALYPSO, comparing carboplatin and paclitaxel with a combination of carboplatin and pegylated liposomal doxorubicin in platinum-sensitive disease. This trial is being conducted as a ‘non-inferiority’ trial and will focus on the relative side effects of the two combinations.
Platinum-resistant ovarian cancer
Eventually, all women with recurrent ovarian cancer develop platinum-resistant disease. In some this occurs after first-line therapy but, for the majority, it is after several lines of treatment. Not all women are fit for further chemotherapy or want to receive it. However, a modest benefit can be gained from drugs such as pegylated liposomal doxorubicin, taxanes (in taxane-naïve cases) or topotecan. These three agents have been evaluated in randomised trials and reviewed by the National Institute for Health and Clinical Excellence (NICE). The NICE guidance14 recommends the use of topotecan in cases where liposomal doxorubicin or taxanes are considered inappropriate. Oral etoposide is probably no less active than the others but has not been studied in randomised controlled trials. It is used quite frequently ‘off licence’. There is currently no evidence that combinations of these drugs are superior to single-agent therapy but trials studying this approach are under way.
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Dose-dense chemotherapy
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Dose-dense chemotherapy is being tested to find out whether it will increase the modest results of single-agent therapy in the platinum-resistant group. There is some evidence of an increased benefit for dose-dense (weekly) delivery of platinum. Weekly cisplatin is less myelotoxic than carboplatin and has been combined with oral etoposide. There are laboratory data to suggest a synergistic effect, with etoposide inhibiting the repair of cisplatin-induced DNA damage. In the study reported by van der Burg et al.15 a response rate of 46% (90% among platinum-sensitive women) and a complete response of 28% were seen, with a median progression-free survival of 5 months (range 2–41 months) and overall survival of 11 months (range 2–41 months). The toxicity of this regimen is variable and requires careful selection of patients.
The effect of weekly paclitaxel has also been studied. There have been reports that it may have greater activity and less toxicity when administered weekly at lower doses. Response rates of 25–50% have been reported when using 80 mg/m2/week. It has also been combined with weekly platinum. In one study16 of weekly induction therapy with carboplatin AUC 4 and paclitaxel 90 mg/m2, there was a response in 53% of women with a platinum-free interval (PFI) <6 months and in 80% of those with a PFI >6 months. Grade 3 or 4 neutropenia occurred in 31%, but fever in only 1.7% of cases.
Weekly platinum-based chemotherapy seems an attractive approach in platinum-resistant cases, but it may also have a role in platinum-sensitive cases: a randomised trial comparing weekly with 3-weekly regimens is needed.
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Intraperitoneal chemotherapy
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As ovarian cancer is usually confined to the abdominal cavity, intraperitoneal therapy has been pursued enthusiastically by several groups for many years. The approach is particularly appealing in situations where the residual disease in the peritoneal cavity is small and more easily penetrated by drugs given via the intraperitoneal route. Three platinum-based trials17–19 have demonstrated a survival advantage over intravenous therapy. This has led to a clinical announcement by the National Cancer Institute20 recommending that intraperitoneal therapy should be considered for women with small-volume residual disease after surgery. The recent GOG 172 trial19 reported a median survival difference of 16 months, from 49.7 to 65 months (P=0.03) after intraperitoneal therapy compared with that after intravenous chemotherapy alone. In this trial cisplatin and paclitaxel were administered intraperitoneally. Both drugs have been shown to have a pharmacological advantage by this route. However, the experimental arm in all three trials differed. Furthermore, toxicity in multicentre practice has been significant and includes catheter-related problems, abdominal pain, infection and gastrointestinal disturbance. Only 42% of women were able to complete all planned cycles of intraperitoneal therapy in the recent GOG trial,19 mainly because of toxicity. At this time it is difficult to know what the optimum intraperitoneal drug treatment should be and no regimen has been directly compared with ‘standard’ intravenous carboplatin and paclitaxel. More studies are required and greater experience needs to be gained in cases of small-volume residual disease to determine the place of this treatment in the management of ovarian cancer.
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Novel agents
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There is considerable interest in non-cytotoxic targeted therapy in cancer treatment, and ovarian cancer is no exception (Table 1). Targeting the HER2 receptor with trastuzumab, which has been so successful in breast cancer, has been relatively ineffective in ovarian cancer, as amplification of the ERBB2 gene is uncommon. Targeting and inhibiting epidermal growth factor receptor (EGFR) tyrosine kinase and promoting apoptosis is an area of current research. An international phase III trial, led by the EORTC (55041) is under way using erlotinib and oral EGFR inhibitor, administered after primary chemotherapy with carboplatin and paclitaxel. A non-randomised phase II study using bevacizumab to target vascular endothelial growth factor (VEGF) has led to tumour responses and prolonged disease stabilisation among heavily pre-treated women. However, there is some concern about toxicity, with reports21,22 of fatal bowel perforation in some cases, particularly in those with extensive peritoneal disease. Bevacizumab is being studied in the first-line setting with carboplatin and paclitaxel, added during and after chemotherapy, in two similar large trials conducted by the US and European groups (GOG 218 and ICON 7).
For women in first relapse, the ICON 6 will compare platinum and paclitaxel with or without the anti-VEGFR (vascular endothelial growth factor receptor) inhibitor AZD 2171(cediranib). The study will investigate the use of this oral agent in chemotherapy and as maintenance treatment after completion of chemotherapy. There is also an ongoing randomised feasibility study in the UK of maintenance with BIBF 1120, a triple kinase inhibitor, for women who have responded to relapse therapy.
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Conclusion
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Chemotherapy has an established and important role in the management of ovarian cancer. Carboplatin and paclitaxel remain standard care for first-line therapy. There is still uncertainty about the best timing of chemotherapy in relation to surgery and debate continues about the benefit of intraperitoneal treatment. Careful selection of the many drugs that are active in ovarian cancer, and their scheduling, are particularly important for the management of relapsed disease. The availability of antibodies and small molecules targeting cell surface receptors, intracellular kinases and angiogenesis has opened up many new therapeutic possibilities. Important multinational trials of these agents, alone or in combination with chemotherapy, are under way. The objectives of these studies are to increase the proportion of women cured, to extend life by prolonging disease remission or to control through intermittent or continuous therapy.
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References
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TOP
Abstract
Introduction
