What are the harms and benefits of using pegylated liposomal doxorubicin in women with recurrent epithelial ovarian cancer, alone or in combination with other drugs?

What is the aim of this review?

The aim of this Cochrane Review update was to summarise benefits and unwanted effects of using a coated form of a chemotherapy drug, pegylated liposomal doxorubicin (PLD), for treatment of women with epithelial ovarian cancer (EOC) that had progressed/returned after initial treatment. The review authors collected and analysed all relevant studies to answer this question and found 26 studies, adding 12 studies to the original version of this review.

Key messages

Women whose EOC returned more than six months after finishing their last treatment who were treated with PLD alongside other chemotherapy survived for a similar length of time to women treated with alternative combinations. It may also take longer for their cancer to re-grow than with alternative combinations. Quality of life may slightly improve with PLD treatment. Apart from anaemia, which was more common in women taking the PLD treatment, severe side effects were similar to those seen in women on alternative combinations.

In women whose EOC returned within six months of finishing their last platinum treatment, PLD alongside other chemotherapy, versus alterative combination chemotherapy, probably works as well in terms of improving how long they live, but we are uncertain about other unwanted effects and benefits. PLD alongside other chemotherapy versus PLD alone likely makes little difference in how long women survive, and may make little difference in how long it takes for their cancer to re-grow, but the combination likely increases overall severe unwanted effects and the risk of severe anaemia.

What was studied in this review?

The choice of chemotherapy in women with relapsed EOC is influenced by the duration of platinum-free interval (length of time from the last platinum-based chemotherapy to the time of disease progression). This is because a short 'platinum-free interval' suggests that their disease will no longer respond to platinum-based chemotherapy. Women who relapse within one month of receiving platinum therapy, or who progress on therapy have 'platinum-refractory' disease; women who relapse between one and six months after platinum therapy have 'platinum-resistant' disease; and women who relapse more than six months after platinum therapy have 'platinum-sensitive' disease.

Doxorubicin hydrochloride is an anti-cancer drug that works by interfering with cancer cell DNA. However, it can have unwanted effects on the heart. Coating the drug within a protective shell allows it to reach higher concentrations in cancer cells whilst protecting the heart. This coated chemotherapy is called pegylated liposomal doxorubicin (PLD).

We wanted to determine how PLD could be used best in women with EOC that has returned, Most of these women will have a limited life expectancy, so consideration of quality of life is important in making treatment choices. One specific side effect of PLD is called hand-foot syndrome (HFS). This is reddening, swelling, numbness and skin peeling of the palms of the hands and soles of the feet.

What are the main results of the review?

We added 12 studies to the previous review, so now include 26 studies with a total of 8277 women with recurrent EOC. Seven studies looked at platinum-sensitive disease (2827 women); 11 platinum-resistant disease (3246 women); and eight recruited women who had both platinum-sensitivity and platinum resistant disease (2079 women).

Recurrent platinum-sensitive EOC

We found five studies for women with platinum-sensitive disease using PLD in combination with chemotherapy versus alternative combination chemotherapy. The PLD combination likely makes little difference in how long women survive (overall survival, OS), but likely increases the time to further relapse (progression-free survival, PFS). There may be a slight improvement in quality of life. There may be little to no difference in the overall number of severe unwanted effects, although adding PLD causes more anaemia. We are uncertain about the effect of PLD with chemotherapy on other individual unwanted effects.

Recurrent platinum-resistant EOC

We found six studies for women with platinum-resistant disease using PLD alone compared to conventional chemotherapy. PLD alone likely makes little difference in OS. We are very uncertain about the effect on PFS, overall severe unwanted effects (i.e. those that require hospital treatment, e.g. blood transfusion), severe anaemia (grade ≥ 3), HFS, and the rate of severe unwanted effects on the nervous system (e.g. permanent numbness in fingers and toes).

We found two studies that compared PLD alongside other chemotherapy combination with PLD alone. PLD in combination likely makes little difference in OS, and it may make little difference in PFS. The combination likely increases overall severe unwanted effects and anaemia. Combination treatment likely results in a large reduction in HFS, but may result in little difference in unwanted effects on the nervous system.

Several studies compared PLD alone with new targeted agents or immunotherapy, but we are very uncertain about the benefit of adding these to PLD.

How up to date is this review?

We searched electronic databases and other resources for studies of PLD for relapsed EOC, and included 26 studies up to January 2022.

Authors' conclusions: 

In platinum-sensitive relapsed EOC, including PLD in a combination chemotherapy regimen probably makes little to no difference in OS compared to other combinations, but likely improves PFS. Choice of chemotherapy will therefore be guided by symptoms from previous chemotherapy and other patient considerations. Single-agent PLD remains a useful agent for platinum-resistant relapsed EOC and choice of agent at relapse will depend on patient factors, e.g. degree of bone marrow suppression or neurotoxicity from previous treatments. Adding another agent to PLD likely increases overall grade ≥ 3 adverse events with little to no improvement in survival outcomes. The limited evidence relating to PLD in combination with other agents in platinum-resistant relapsed EOC does not indicate a benefit, but there is some evidence of increased side effects.

Read the full abstract...
Background: 

Cancer of ovarian, fallopian tube and peritoneal origin, referred to collectively as ovarian cancer, is the eighth most common cancer in women and is often diagnosed at an advanced stage. Women with relapsed epithelial ovarian cancer (EOC) are less well and have a limited life expectancy, therefore maintaining quality of life with effective symptom control is an important aim of treatment. However, the unwanted 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 treatment of relapsed EOCs. This is an update of the original Cochrane Review which was published in Issue 7, 2013.

Objectives: 

To evaluate the efficacy and safety of PLD, with or without other anti-cancer drugs, in women with relapsed high grade epithelial ovarian cancer (EOC).

Search strategy: 

We searched CENTRAL, MEDLINE (via Ovid) and Embase (via Ovid) from 1990 to January 2022. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.

Selection criteria: 

We included randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer.

Data collection and analysis: 

Two review authors independently extracted 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.

Main results: 

This is an update of a previous review with 12 additional studies, so this updated review includes a total of 26 RCTs with 8277 participants that evaluated the effects of PLD alone or in combination with other drugs in recurrent EOC: seven in platinum-sensitive disease (2872 participants); 11 in platinum-resistant disease (3246 participants); and eight that recruited individuals regardless of platinum sensitivity status (2079 participants). The certainty of the evidence was assessed for the three most clinically relevant comparisons out of eight comparisons identified in the included RCTs.

Recurrent platinum-sensitive EOC

PLD with conventional chemotherapy agent compared to alternative combination chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.83 to 1.04; 5 studies, 2006 participants; moderate-certainty evidence) but likely increases progression-free survival (PFS) (HR 0.81, 95% CI 0.74 to 0.89; 5 studies, 2006 participants; moderate-certainty evidence). The combination may slightly improve quality of life at three months post-randomisation, measured using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (mean difference 4.80, 95% CI 0.92 to 8.68; 1 study, 608 participants; low-certainty evidence), but this may not represent a clinically meaningful difference.

PLD in combination with another chemotherapy agent compared to alternative combination chemotherapy likely results in little to no difference in the rate of overall severe adverse events (grade ≥ 3) (risk ratio (RR) 1.11, 95% CI 0.95 to 1.30; 2 studies, 834 participants; moderate-certainty evidence). PLD with chemotherapy likely increases anaemia (grade ≥ 3) (RR 1.37, 95% CI 1.02 to 1.85; 5 studies, 1961 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of PLD with conventional chemotherapy on hand-foot syndrome (HFS)(grade ≥ 3) (RR 4.01, 95% CI 1.00 to 16.01; 2 studies, 1028 participants; very low-certainty evidence) and neurological events (grade ≥ 3) (RR 0.38, 95% CI 0.20 to 0.74; 4 studies, 1900 participants; very low-certainty evidence).

Recurrent platinum-resistant EOC

PLD alone compared to another conventional chemotherapy likely results in little to no difference in OS (HR 0.96, 95% CI 0.77 to 1.19; 6 studies, 1995 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of PLD on PFS (HR 0.94, 95% CI 0.85 to 1.04; 4 studies, 1803 participants; very low-certainty evidence), overall severe adverse events (grade ≥ 3) (RR ranged from 0.61 to 0.97; 2 studies, 964 participants; very low-certainty evidence), anaemia (grade ≥ 3) (RR ranged from 0.19 to 0.82; 5 studies, 1968 participants; very low-certainty evidence), HFS (grade ≥ 3) (RR ranged from 15.19 to 109.15; 6 studies, 2184 participants; very low-certainty evidence), and the rate of neurological events (grade ≥ 3)(RR ranged from 0.08 to 3.09; 3 studies, 1222 participants; very low-certainty evidence).

PLD with conventional chemotherapy compared to PLD alone likely results in little to no difference in OS (HR 0.92, 95% CI 0.70 to 1.21; 1 study, 242 participants; moderate-certainty evidence) and it may result in little to no difference in PFS (HR 0.94, 95% CI 0.73 to 1.22; 2 studies, 353 participants; low-certainty evidence). The combination likely increases overall severe adverse events (grade ≥ 3) (RR 2.48, 95% CI 1.98 to 3.09; 1 study, 663 participants; moderate-certainty evidence) and anaemia (grade ≥ 3) (RR 2.38, 95% CI 1.46 to 3.87; 2 studies, 785 participants; moderate-certainty evidence), but likely results in a large reduction in HFS (grade ≥ 3) (RR 0.24, 95% CI 0.14 to 0.40; 2 studies, 785 participants; moderate-certainty evidence). It may result in little to no difference in neurological events (grade ≥ 3) (RR 1.40, 95% CI 0.85 to 2.31; 1 study, 663 participants; low-certainty evidence).

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