Ovarian cancer: platinum-based therapy still the gold standard
SummaryDespite being the most common cause of death from gynecological tumors, ovarian cancer does not attract the same level of R&D interest as more prevalent tumor types. While surgery still plays a central role in the treatment of ovarian cancer, platinum-based therapy, in particular, carboplatin in combination with paclitaxel, remains the mainstay of cytotoxic treatment for ovarian cancer.
Nearly 60,000 cases of ovarian cancer are being diagnosed in the seven major markets each year, and although five-year survival rates have been trending upwards, prognosis deteriorates as the disease progresses until by stage IV, the five year survival rate is below 20%.
Surgery remains important
As in other tumor types, surgery remains central to the management of ovarian cancer, even in more advanced stages of the disease. While cytoreduction of tumor mass is correlated to patient prognosis, some stage III patients who are poor surgical candidates may be considered for neoadjuvant chemotherapy prior to debulking surgery. The chemotherapy prior to surgery is designed to reduce the size of the tumor before it is removed.
However, as ovarian cancer progresses, drug therapy plays a more key role in treating the disease. It is only in recent times that second- and third-generation cytotoxics have become integral to managing the disease, and it is one of the reasons for an upward trend for five-year survival rates of ovarian cancer between 1975 and 1997 in the US, improving at a compounded annual growth rate of 1.2%.
Nevertheless, prognosis deteriorates as the disease progresses and by stage IV, where the treatment is usually palliative (aimed at ensuring a better quality of life, rather than being curative), five-year survival rate is down to less than 20%.
Until the mid-1990s, the standard of care for ovarian cancer was based on a platinum drug combined with an alkylating agent, typically cyclophosphamide. However, the treatment paradigm shifted after major clinical trials showed the clinical superiority of cisplatin in combination with paclitaxel compared with cisplatin plus cyclophosphamide.
Once the clinical efficacy of cisplatin plus paclitaxel was established, the next task which fell upon the researchers was to determine the superiority of the different platinum agents, namely cisplatin and carboplatin. The superior uptake of carboplatin-based regimens for ovarian cancer has mainly been based on the more favorable toxicity profile and convenient administration schedule of the drug compared with cisplatin.
Given the proven efficacy of cisplatin and paclitaxel, there may be potential for other platinum drugs such as Sanofi-Aventis's Eloxatin (oxaliplatin) for ovarian cancer. While ovarian cancer doesn't attract the same level of R&D investment as breast or lung cancer for example, it remains an important secondary indication for existing and pipeline drugs.
Paclitaxel dominates as a partner drug for carboplatin. Sanofi-Aventis' Taxotere (docetaxel) has been shown to be as efficacious as paclitaxel but it remains unapproved for ovarian cancer. There are also other drugs such as Eli Lilly's Gemzar (gemcitabine), GlaxoSmithKline's Hycamtin (topotecan) and Ortho Biotech/Schering Plough's Doxil/Caelyx (liposomal doxorubicin) that feature in the pharmacological management of ovarian cancer at various stages, but none have produced significant clinical advantages over another.
Similarly, there are a number of cytotoxic drugs in late-stage development for ovarian cancer such as Cell Therapeutics' Xyotax (polyglutamate paclitaxel) and Novartis's Patupilone (epothilone), but none are likely to change the treatment paradigm for ovarian cancer.
Instead, Genentech/Roche's Avastin (bevacizumab) is expected to make a significant impact in the ovarian cancer market. According to physicians in the US, Avastin is used significantly off label in second line treatment despite the halting of a phase II trial in that setting due to a higher-than-expected incidence of gastrointestinal perforations.
Genentech and Roche are continuing with a phase III study of Avastin in first line and an approval in that setting will likely spur considerable use of the drug for ovarian cancer.