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Department of Gynaecology and Obstetrics
University Clinic Schleswig-Holstein
Ovarian cancer is the fifth most common malignancy in women, and is usually diagnosed at an advanced stage of disease. In the USA approximately 22,000 new cases occur each year.(1) In Germany about 8,000 new cases of ovarian cancer are diagnosed each year. Among these patients, the vast majority (>75%) are diagnosed with advanced-stage disease (FIGO III/IV) with an unfavourable prognosis; this is because of the lack of early and specific symptoms. Consequently, only about 25% of patients are diagnosed at a stage where the malignancy is still confined to the ovary or lower pelvis. These cases – carrying a good prognosis, with a five-year survival of up to 90% – are often diagnosed accidentally when the adnexa is removed because of ovarian cysts.
No valid screening tool for ovarian cancer is available until today; sequential vaginal ultrasound is not reliable enough, not even in patients at high risk, due to BRCA I or II mutations. Also, no blood test shows a suitable level of specificity or sensitivity, whether the CA-1252 or any other protein profiling,(3) to be established as a routine screening marker for ovarian cancer. We have recently shown that the combination of several secreted markers (osteopontin/kallikrein/MMP7) in combination with CA-125 could highly accurately distinguish sera of ovarian cancer patients from those of healthy women. Although this blood test was also able to detect early-stage disease, further validation is still necessary.(4)
The most important prognostic marker for survival of advanced ovarian cancer patients remains the postoperative tumour burden.(5) No medical therapy is able to compensate for an inadequate surgical procedure; therefore, patients suspected of having ovarian cancer should be referred to specialist centres.
In the mid 1990s, the Gynecologic Oncology Group (GOG) study III6 showed that cisplatin in combination with paclitaxel was superior to cisplatin and cyclophosphomide with respect to disease-free survival (DFS) and overall survival (OS) (18 vs 12.9 months and 37 vs 24 months, respectively).
Three prospective randomised trials proved the efficacy of paclitaxel in combination with platinum derivates.(7-9) The combination of cisplatin and paclitaxel and carboplatin and paclitaxel showed similar values for time to progression and OS (see Figure 1).
However, comparing the side-effects, the combination with carboplatin was less neurotoxic than the cisplatin-based regimen. Therefore, quality of life is significantly improved by using carboplatin instead of cisplatin.(10) Consequently, today’s standard primary chemotherapy in ovarian cancer treatment is the combination of carboplatin and paclitaxel, which provides the best ratio of benefits and side-effects.(11)
In order to improve the gold standard with respect to DFS and OS, one option could be the incorporation of non-crossresistant cytotoxic drugs into carboplatin and paclitaxel. Several such attempts have been made with different drugs in recent years. Adding epirubicine did not show prolonged progression-free survival (PFS) or OS but increased haematological and nonhaematological side-effects.(12,13) Also, the combination of carboplatin, paclitaxel and topotecan as sequential single agent did not improve patients’ outcome (see Figure 2).(14,15)
Incorporating liposomal pegylated doxorubicin and gemcitabine did not add benefits to the patients’ survival.(16)
So far, no improvement has been achieved by adding a third non-crossresistant conventional cytotoxic agent (eg, topotecan/etoposide/pegylated liposomal doxorubicin or gemcitabine).
Another option to optimise treatment might be using different routes to administer the chemotherapeutic agents. In the recently published GOG172 study,(17) patients received the chemotherapy intravenously (IV) and intraperitoneally (IP). Patients treated in the standard arm received the combination cisplatin (75mg/m2) and paclitaxel (135mg/m2) IV. In contrast, patients treated in the experimental arm received paclitaxel (135mg/m2) on day 1 IV, cisplatin (100mg/m2) IP on day 2 and additionally paclitaxel (60mg/m2) on day 8 IP.
The authors report a significant advantage for median survival for the IP group, with 65.6 months vs 49.7 months compared to the IV group. No significant difference was found for PFS, but the patients treated in the IP arm did have a significant disadvantage with respect to quality of life (eg, abdominal pain, neurotoxicity). Only 42% of the patients completed the IP regimen as planned; even in experienced cancer centres, 8% of the patients obtained no IP chemotherapy at all and in 34% of the patients only one to two cycles of IP chemotherapy were given. However, it is difficult to interpret the results. One might criticise the different dosages of cisplatin used (75mg/m2 vs 100mg/m2).
Also, the additional application of paclitaxel on day 8 raises the question of whether it would be useful to employ a dose-dense regimen rather than giving chemotherapy IP.
Additionally, this was not an intention-to-treat analysis. No data on second-line treatment are published; this fact may be very important, since it is well known that second-line treatment has an impact on survival. Thus, this regimen has not been adopted as standard of care.
Identifying biological dependencies of ovarian cancers which could be targeted specifically may be one option to improve DFS and OS in ovarian cancer patients. In recent years, more and more specific antibodies and small molecules have become available for targeted therapy. For ovarian cancer patients, the therapeutic intervention could be a combination of carboplatin and paclitaxel plus a small-molecule drug. Targeting tumour-induced neoangiogenesis could be one option.
The humanised VEGF antibody bevacizumab shows clinical responses in heavily pretreated ovarian cancer patients.(18-21) Trials that include bevacizumab are recruiting. In these trials, the drug will be given for one year every three weeks.
In a phase II study, erlotinib showed marginal activity but was well tolerated. Interestingly, the survival rate correlated significantly with the skin rash grade induced by erlotinib; patients with higher grades of skin rashes survived longer.(22) Also, erlotinib is currently being investigated in a phase III clinical trial, given as maintenance therapy after primary chemotherapy. In phase I clinical trials, the anti-idiotypic antibody abagovomab (CA 125 antigen) in patients with recurrent ovarian cancer was found to be safe and was also well tolerated.(23,24) Thus, this agent is also currently under investigation in a phase III study.
Imatinib was used in the recently conducted SWOG (S0211) trial in recurrent platinum-resistant ovarian cancers but did not show a markedly improved response rate.(25) Using the small-molecule drug gefitinib in epithelial ovarian cancer also did not result in a clinical response. However, at molecular level, a decrease in target phosphorylation was observed.(26)
Although these data are preliminary, they suggest that, rather than a single-agent therapy, the combination of conventional chemotherapy and targeted therapy might increase chemotherapy responses, prolong DFS and therefore improve the prognosis of ovarian cancer. These specific drugs could also be used as a maintenance therapy option, somewhat equivalent to adjuvant antioestrogen therapies in breast cancer.
Today, the combination of radical cytoreductive surgery and chemotherapy with carboplatin and paclitaxel IV is the standard treatment for advanced ovarian cancer patients.
Much hope is pinned on targeted therapies utilising novel molecular drugs, and several phase III trials with these substances have already been started all around the world. â–
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AGO Ovarian Carcinoma Study Group