Background
The choice of chemotherapy in women with relapsed epithelial ovarian cancer (EOC) is influenced by the duration of the platinum-free interval, the length of time from the last platinum-based cycle to the time of disease progression. Women who relapse within one month of receiving platinum therapy or who progress on therapy are considered to be platinum-refractory; women who relapse between one and six months after platinum therapy are considered to be platinum-resistant; and women who relapse more than six months after platinum therapy are considered to be platinum-sensitive. The latter group is further subgrouped by women who relapse between six and 12 months after platinum therapy (partially platinum-sensitive) and those who relapse after 12 months.
Doxirubicin hydrochloride is an anti-cancer drug that works by interfering with cancer cell DNA. A newer form of doxorubicin called pegylated liposomal doxorubicin (PLD) has been developed with a coating that allows it to reach higher concentrations in cancer cells and with less adverse effects on the heart.
Review question
We conducted this review to determine whether PLD was effective and safe compared with other drugs used for relapsed EOC.
Main findings
We searched electronic databases and other resources for studies of PLD for relapsed ovarian cancerEOC, and included 14 studies up to October 2012. Most of these studies (12/14) were funded by drug manufacturers with a commercial interest in PLD (two studies) or the comparator drugs (10 studies). For women with platinum-sensitive relapsed EOC, we pooled data from two studies (1164 participants) that compared carboplatin plus PLD (PLD/carbo) with standard treatment (paclitaxel plus carbo (PAC/carbo)). Women survived for a similar length of time overall on these two treatments but the cancer took longer to progress in those receiving PLD/carbo. Women who received PLD experienced more severe low blood cell counts than the standard treatment. By comparison, women in the standard treatment group experienced more severe hair loss, nerve damage, allergic reactions, and joint and muscle pain. More women in the standard treatment group stopped treatment early suggesting that PLD/carbo was better tolerated than standard treatment. We concluded that PLD/carbo was a better treatment option than PAC/carbo for platinum-sensitive relapsed EOC.
Five studies compared PLD to five other chemotherapy drugs. The numbers of participants in these studies ranged from 97 to 829 women and we did not pool these data. PLD worked as least as well as the other agents and was comparatively well-tolerated. In all studies, hand-foot syndrome (HFS: swollen, painful, red, cracked and peeled soles and palms) occurred more frequently in the PLD group.
Three studies compared PLD plus another drug (canfosfamide (CAN), vintafolide (EC145) or trabectedin (TBD)) to PLD alone. The final results of the CAN study were not reported. The numbers of participants in the other studies ranged from 149 to 672 women and we did not pool these data. Women receiving the PLD/TBD combination treatment progressed six weeks later than those getting PLD only, however they did not live longer overall, and the combination treatment was associated with additional harmful effects. EC145 may improve survival in women with platinum-resistant relapsed ovarian cancer when combined with PLD; this combination is currently under investigation in a large trial. Although HFS can be severely disabling, we noted that it occurred much less frequently when lower doses of PLD were used.
Quality of the evidence
We consider the evidence related to the longer time to cancer progression with PLD/carbo for platinum-sensitive relapsed ovarian cancer to be of a high quality. There is currently insufficient evidence to support the use of other PLD combination treatments in relapsed EOC.
In platinum-sensitive relapsed epithelial ovarian cancer, PLD/carbo is more effective than PAC/carbo and is better tolerated; PLD/carbo should therefore be considered as first-line treatment in women with platinum-sensitive relapsed EOC. PLD alone is a useful agent for platinum-resistant relapsed EOC, however it remains unclear how it compares with other single agents for this subgroup and in what order these agents should be used. There is insufficient evidence to support the use of PLD in combination with other agents in platinum-resistant relapsed EOC.
Ovarian cancer is the eighth most common cancer in women and it is usually diagnosed at an advanced stage. The majority of ovarian tumours are epithelial in origin. Women with relapsed epithelial ovarian cancer (EOC) often have a reduced performance status with a limited life expectancy, therefore maintaining quality of life with effective symptom control is the main purpose of treatment. Drug treatment of relapsed disease is directed by the platinum-free interval: relapsed platinum-sensitive disease is usually re-treated with platinum-based therapy and platinum-resistant disease challenged with non-platinum drugs. However, the side-effects of chemotherapy agents may be severe and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride is one of several treatment modalities that may be considered for single-agent treatment of relapsed EOC, or used in combination with other drugs.
To assess the efficacy and safety of PLD in women with relapsed epithelial ovarian cancer (EOC).
We searched the Cochrane Gynaecological Cancer Group (CGCG) trials register, CENTRAL, MEDLINE and EMBASE from 1990 to February 2013. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.
Randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer.
Two review authors independently abstracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses using RevMan 5.2 software.
We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC. Overall survival (OS) was similar for these treatments, however progression-free survival (PFS) was longer with PLD/carbo (1164 participants; hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.74 to 0.97; I² = 7%; P value 0.01). PLD/carbo was associated with significantly more anaemia and thrombocytopenia than PAC/carbo, whereas PAC/carbo was associated with significantly more alopecia, neuropathies, hypersensitivity reactions and arthralgias/myalgias. PLD/carbo was well-tolerated and women receiving this treatment were significantly less likely to discontinue treatment than those receiving PAC/carbo (two studies, 1150 participants; risk ratio (RR) 0.38, 95% CI 0.26 to 0.57; I² = 0%; P < 0.00001).
Five studies compared other agents to PLD alone. None of these agents were associated with significantly better survival or severe adverse-event profiles than PLD. Topotecan and gemcitabine were associated with significantly more haematological severe adverse events than PLD, and patupilone was associated with significantly more severe neuropathies and diarrhoea. Severe hand-foot syndrome (HFS) occurred consistently more frequently with PLD than the other drugs.
Three studies compared PLD combination treatment to PLD alone. Two combinations resulted in a significantly longer PFS compared with PLD alone: trabectedin (TBD)/PLD (one study, 672 women; HR 0.79, 95% CI 0.65 to 0.96; P value 0.02) and vintafolide (EC145)/PLD (one study, 149 women; HR 0.63, 95% CI 0.41 to 0.97; P value 0.04). TBD/PLD appeared to benefit the partially platinum-sensitive subgroup only. Further studies are likely to have an important impact on our confidence in these estimates. TBD/PLD was associated with significantly more haematological and gastrointestinal severe adverse events than PLD alone, whereas EC145/PLD appeared to be well-tolerated.
For platinum-resistant relapsed EOC, the median PFS and OS for single-agent PLD across seven included studies was 15 weeks and 54 weeks, respectively. Severe HFS occurred significantly more frequently in women receiving a 50 mg/m² dose of PLD than those receiving less than 50 mg/m² (17% versus 2%, respectively; P value 0.01).