Intravenous paclitaxel plus antiretroviral therapy (ART) has clear advantages over alternative chemotherapy regimens for the treatment of advanced HIV-related Kaposi sarcoma in low- and middle-income settings, according to the results of a landmark study published in The Lancet. Paclitaxel plus ART was compared to cheaper and easier-to-administer therapies and was found to be superior in terms of progression, overall response and response duration.
“Our results provide support for preferring paclitaxel over a commonly used regimen of bleomycin and vincristine or an oral etoposide regimen as first-line chemotherapy for advanced AIDS-related Kaposi sarcoma in resource-limited settings,” comment the investigators.
However, they acknowledge that making paclitaxel available will be a significant challenge for many health systems, especially in terms of cost, resources and manpower. “Analysis of the cost-effectiveness of different Kaposi sarcoma treatments would further inform national strategies,” they add.
Kaposi sarcoma (KS) is an AIDS-defining malignancy and is caused by a human herpes virus. Although incidence has declined since effective ART became available, it can occur even among people who have apparently effective HIV control. In areas of the world where access to ART is limited, and where both HIV and KS-associated herpes viruses are endemic, it continues to cause significant levels of illness and death. It is the second-most common cancer in both Malawi and Uganda (21% and 13% of all cancer diagnoses in the two countries).
Effective management of advanced AIDS-associated KS requires a combination of ART and chemotherapy, but the most appropriate chemotherapy agents have not been determined in resource-limited settings. In richer countries, the first-line option is pegylated liposomal doxorubicin, with paclitaxel as an alternative. These drugs are costly and rarely used in resource-limited settings. Instead, treatment relies on bleomycin and vincristine, either alone or in combination with non-liposomal doxorubicin. Another option is etoposide, which is taken orally and so has practical advantages.
Because of this ongoing uncertainty, Professor Susan Krown of the AIDS Malignancy Consortium and colleagues from the AIDS Clinical Trials Group designed an open-label, randomised study to compare the effectiveness of three alternative regimens for the treatment of advanced HIV-related KS:
- intravenous bleomycin and vincristine + ART
- oral etoposide + ART
- intravenous paclitaxel + ART.
Study participants were 329 HIV-positive adults with biopsy-confirmed advanced KS (stage T1) who had taken ART for no more than six weeks. Recruitment took place between late 2013 and early 2018 in five African countries and Brazil (14 participants). The median study follow-up was 62 weeks.
Three-quarters of participants were men; median age around 35 years and the median CD4 cell count was around 230.
The primary outcome was a comparison of progression-free survival over 48 weeks with a 15% non-inferiority threshold for intravenous bleomycin/ vincristine and oral etoposide compared to paclitaxel.
The study was stopped early when it became clear that neither of the alternative regimens was non-inferior to paclitaxel and ART. The etoposide arm was terminated in March 2016 and the bleomycin/vincristine arm two years later. The 48 week progression-free survival rate was 50% for paclitaxel plus ART but only 20% for oral etoposide plus ART. Comparison between paclitaxel plus ART versus bleomycin/vincristine plus ART showed a 64% progression-free survival for the former compared to 44% for the latter.
Mortality rates at week 48 were higher for both bleomycin/vincristine and oral etoposide compared to paclitaxel. The median duration of response also favoured paclitaxel over both alternative regimens. There were high rates of HIV suppression and robust increases in CD4 cell counts across all three treatment arms.
Nobody treated with paclitaxel experienced immune reconstitution inflammatory syndrome, while this occurred in 2% of individuals on bleomycin/vincristine and 10% of etoposide-treated patients.
“Not only is paclitaxel more costly than the alternative regimens, but its safe administration requires use of specialised equipment."
Approximately half of participants experienced a moderate-to-serve adverse event, with rates broadly comparable between regimens. However, rates of pain were lower among people taking paclitaxel than either bleomycin/vincristine or oral etoposide. The study allayed fears that paclitaxel would be associated with an unacceptably high burden of neuropathy or neutropenia.
“The study failed to show non-inferiority of either investigational arm compared to paclitaxel plus ART,” comment the authors. “The clinical interpretation is that paclitaxel plus ART is a superior treatment to both oral etoposide plus ART and bleomycin and vincristine plus ART.”
However, the investigators acknowledge that use of paclitaxel will prove challenging for many low- and middle-income countries. “The overall costs of treatment with paclitaxel plus ART are likely to be higher than for alternative regimens evaluated in this study,” conclude Dr Krown and her colleagues. “Not only is paclitaxel generally more costly than the alternative regimens, but its safe administration requires use of specialised filters and pre-medications to prevent hypersensitivity reactions, further increasing the costs of treatment. Thus, it remains to be seen whether adopting paclitaxel plus ART as the standard of care would be a cost-effective use of resources.”
The cost of paclitaxel in Malawi was previously reported to be $580 (compared to bleomycin/vincristine at $335), although its cost should now be lower in six African countries included in market access agreements negotiated by the Clinton Health Access Initiative. It is on the World Health Organization's list of essential medicines.
An accompanying editorial by Dr Esther Freeman and colleagues commended the study. They note the survival rates associated achieved with paclitaxel were comparable to those achieved in richer countries. However, they also note several challenges that need to be overcome for this treatment to become a viable option for many resource-limited countries: cost, scaling up of oncology services and availability of generics.
Krown SE et al. Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label randomised, non-inferiority trial. The Lancet, 395: 1195-1207, 2020 (open access).
Freeman EE et al. Time to address disparities in the standard of care for Kaposi sarcoma. The Lancet, 395: 1169-70, 2020.