GeDDiS Findings Support Doxorubicin For First-Line Advanced Soft-Tissue Sarcoma

Survival outcomes are comparable, but toxicity greater, with gemcitabine plus docetaxel versus doxorubicin for treatment-naïve advanced soft-tissue sarcoma

medwireNews: Doxorubicin should remain the standard of care for the first-line treatment of advanced soft-tissue sarcoma, say the GeDDiS trial investigators who found no survival gain with an alternative gemcitabine plus docetaxel regimen.

“Although the observed similar progression-free survival and overall survival of gemcitabine and docetaxel and doxorubicin might support a conclusion that either schedule can be used according to patient or clinician preference, our results indicate the need for caution with such an approach given the greater difficulty in delivery and toxicity of gemcitabine and docetaxel, and indeed the higher cost of this combination regimen”, the researchers recommend in The Lancet Oncology.

However, William Tap, from Memorial Sloan Kettering Cancer Institute in New York, USA, suggests in an accompanying comment that this conclusion is “debatable”. He believes that “[t]he results of the GeDDiS trial should allow individual clinicians to determine how to position and in what clinical context to use gemcitabine and docetaxel for the care of their patients.”

The primary endpoint of the proportion of patients alive and progression-free at week 24 was a comparable 46.3% and 46.4% for the 129 patients randomly assigned to receive six 3-week cycles of doxorubicin 75 mg/m2 given on day 1 and the 128 patients who were given six 3-week cycles of gemcitabine 675 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8, respectively.

Overall survival was similar in the doxorubicin and gemcitabine plus docetaxel groups, at a median of 76.3 weeks and 67.3 weeks, respectively, as was median progression-free survival at a corresponding 23.3 and 23.7 weeks.

And preplanned exploratory analysis of histological subgroups failed to find a difference in patient outcomes, including between patients with leiomyosarcoma or uterine leiomyosarcoma versus other forms of the disease.

“This finding shows that that the inclusion of patients with leiomyosarcoma (46% of patients) did not drive the data in a specific direction”, writes William Tap. “It also argues for equipoise in consideration for either doxorubicin or gemcitabine and docetaxel as a first-line treatment for patients with soft-tissue sarcomas including leiomyosarcoma.”

Nevertheless, the researchers note that patients given the doxorubicin regimen were more likely to complete their planned treatment than their counterparts given gemcitabine plus docetaxel, with 56% versus 39% of patients receiving all six cycles.

Doxorubicin-treated patients were also less likely to experience a dose delay (46 vs 56%) or stop treatment because of toxicity (1 vs 10%), although the doxorubicin regimen was associated with a higher rate of dose reductions (27 vs 18%).

The most common grade 3–4 events in the doxorubicin and the gemcitabine plus docetaxel groups were neutropenia (25 vs 20%), febrile neutropenia (20 vs 12%), fatigue (6 vs 14%), oral mucositis (14 vs 2%) and pain (8 vs 10%).

And the three most common serious adverse events, accounting for 39% of the collated 155 recorded in the doxorubicin arm and the 130 in the gemcitabine plus docetaxel arm, were febrile neutropenia (17 vs 12%), fever (12 vs 15%) and neutropenia (14 vs 8%).

Discussing their evidence in support of doxorubicin remaining the standard of care, lead investigator Beatrice Seddon, from University College London Hospitals NHS Foundation Trust in the UK, and team comment: “There might of course be occasions when different choices are made depending on patient factors and preferences, such as using combination doxorubicin and ifosfamide for selected patients who need to optimise chances of tumour shrinkage, or using gemcitabine and docetaxel in patients with cardiac dysfunction that contraindicates use of doxorubicin.”

They add: “The study also highlights the importance of doing randomised trials in rare cancers to rigorously compare new treatments with established standard treatments, rather than extrapolating promising results from smaller non-comparative trials.”

References

Seddon B, Strauss SJ, Whelan J, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcoma (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol; Advance online publication 4 September 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30622-8

Tap WD. GeDDiS: insight into frontline therapy in soft tissue sarcoma. Lancet Oncol; Advance online publication 4 September 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30672-1

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