Long-term Survival Advantage for Recurrent Ovarian Cancer Patients Receiving Pegylated Liposomal Doxorubicin
Alan N Gordon, MD Clinical Professor of Obstetrical Gynecology, University of Arizona School of Medicine
Ovarian cancer remains the leading cause of death from gynecologic malignancies.Although endometrial cancer occurs more frequently, the vast majority of patients who develop this disease present with postmenopausal or other irregular bleeding problems and are usually diagnosed with early-stage disease and experience long survival. In contrast, the presenting signs and symptoms of ovarian cancer are nonspecific, and almost 75% of patients already have extensive abdominal disease at the time of diagnosis (stage IIIC and IV). The failure to be able to detect ovarian cancer at earlier stages has lead to it being labeled as ‘the silent killer’.
The use of extensive debulking procedures, which may include resections of the gastrointestinal or urinary tracts, can decrease the tumor burden for cytotoxic chemotherapy and help to prolong survival. The addition of taxanes to platinum-based therapy have lead to significant improvement in both progression-free and overall survival in patients with either optimally reduced or sub-optimally reduced advanced-stage disease. Currently, ovarian cancer patients are living longer, and as the disease tends to remain within the peritoneal cavity without affecting vital organs, patients may maintain a good performance status for a long time. Unfortunately, disease usually relapses. Relapse may be heralded by elevation of CA-125, and eventually symptoms and evidence of disease will appear, leading to treatment of recurrent disease. With patients living longer and receiving therapy for longer periods of time, there is a need for agents that are well tolerated, lacking of cumulative toxicity, and able to maintain quality of life rather than worsen it due to unintended side effects.
Treatment at time of relapse has been guided by the interval from the patients’ prior platinum exposure. Those patients who had demonstrated progression of disease while on platinum-based therapy, or relapsed within six months from their last platinum therapy,were thought to be platinum resistant and should be treated with other non-cross-resistant agents. Patients who had initially responded and demonstrated clinical progression more than six months after their last platinum therapy were thought to have potentially platinum-sensitive disease, and would be re-treated with platinum agents. The probability of responding to retreatment increases with time from the last platinum exposure. After a platinum-free interval of two years, response rates may approach 60%, which is similar to initial response rates in untreated disease. Although response rates at earlier intervals were lower, prior to the late 1990s there were no agents that were thought to have significant activity in relapsed ovarian cancer, and platinum-based therapy was the standard.
Paclitaxel did exhibit activity in recurrent ovarian cancer but, based on several studies, quickly moved into first-line therapy as part of a taxane and platinum-based combination. Then, several agents in phase II trials showed promising activity in relapsed ovarian cancer.A phase III trial, comparing topotecan with paclitaxel, showed statistically equivalent response rates and survival data in paclitaxel naïve patients. Based largely on this data, topotecan was approved for use in relapsed ovarian cancer by the US Food and Drug Administration (FDA). Phase II trials with pegylated liposomal doxorubicin (PLD) that had been underway had shown activity for PLD in platinum refractory ovarian cancer. It was then decided to proceed with a phase III trial comparing PLD with topotecan.
The results of this phase III trial were initially reported in 2001. There were 474 patients enrolled from 104 sites from around the world. Patients were stratified upon enrollment based on platinum sensitivity or resistance and on the presence or absence of bulky disease. There was no difference in response rates in the overall or any sub-group analysis. In the survival data that were available, there was no difference in progression-free or overall survival for the entire group. However, there was a significant improvement in progression-free survival and an even greater improvement in overall survival for the platinum-sensitive patients initially treated with PLD. There was a large number of censored events as many of the patients had not progressed or died at the time of the report. After more than 90% of the patients had recurred or died, a planned updated analysis was performed, to reevaluate the survival data.
