In practice, doxorubicin alone is often not used as the first-line standard of care for soft tissue sarcomas; however, a lack of high-quality survival data precludes other regimens becoming the gold standard
Single-agent doxorubicin has a level I, grade A recommendation in the latest ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for advanced soft tissue sarcomas (STS) (Ann Oncol. 2021;32:1348–1365); however, its position as standard first-line therapy is far from clear cut in clinical practice according to Prof. Peter Reichardt from the Sarcoma Center, Helios Hospital Berlin Buch, Berlin, Germany.
“When previous studies have been conducted to search for better regimens than doxorubicin alone – for example, doxorubicin-based combinations or alternative single-agent treatments – design issues resulted in a failure to show significant overall survival (OS) benefits,” he says anticipating some of the critical aspects discussed at the ESMO Sarcoma and GIST Virtual Symposium 2022. “These were basket studies that analysed various STS subtypes together. The overall result was neutral for the new regimens and there was insufficient data on separate subtypes to enable definite conclusions to be made.”
On the positive side, he thinks subtype-specific data are now being generated that challenge the use of single-agent doxorubicin as standard first-line treatment, at least for certain sarcomas. For instance, leiomyosarcoma is one subtype where evidence is growing in favour of combination therapies. A recent analysis by the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group retrospectively evaluated doxorubicin plus dacarbazine, doxorubicin plus ifosfamide and doxorubicin alone as first-line treatments for advanced/metastatic leiomyosarcoma (Cancer. 2020;126:2637–2647). Doxorubicin plus dacarbazine was associated with longer median OS (36.8 months) in comparison with doxorubicin plus ifosfamide (21.9 months) and doxorubicin alone (30.3 months).
New randomised phase III trial data, presented at the ESMO Congress 2021, indicate that another doxorubicin-containing regimen could be superior to doxorubicin alone in metastatic or unresectable leiomyosarcoma (Ann Oncol. 2021;32 suppl_5:S1283–S1346). Results from the LMS-04 trial demonstrated that doxorubicin with trabectedin prolonged the primary endpoint of progression-free survival (PFS) compared with doxorubicin alone (median, 13.5 months versus 7.3 months; adjusted hazard ratio [HR] 0.38; 95% confidence interval [CI] 0.27–0.55; p<0.0001). Furthermore, median OS was 30.5 months with doxorubicin plus trabectedin compared with 24.1 months for doxorubicin alone (HR 0.74; 95% CI 0.49–1.12). Longer-term OS analyses of the LMS-04 trial are awaited.
Other subtypes rely on data from retrospective or subgroup analyses only; combination therapy with doxorubicin plus high-dose ifosfamide appears to be the most active treatment for synovial sarcoma, de-differentiated liposarcomas and peripheral nerve sheath tumours.
Reichardt also questions whether OS is an appropriate benchmark for measuring other regimens against doxorubicin alone in the first-line setting. “In STS, many lines of further therapy have become standard and it is unlikely that a first-line study will result in an OS benefit in some subtypes; however, prolonged PFS is valuable,” he explains. “In the case of multimodality therapy, involving neoadjuvant or adjuvant chemotherapy, it is the significant PFS benefits that have resulted in combination therapies being the standard of care,” he concludes.
Reichardt P. Is doxorubicin still the standard 1st line therapy for all sarcoma subtypes? ESMO Sarcoma and GIST Virtual Symposium 2022
STS 1, 01.02.2022, h. 14:45 – 16:15, Channel 1