No Palifosfamide Benefit For Metastatic Soft Tissue Sarcoma

Combining doxorubicin with palifosfamide does not improve progression-free or overall survival in metastatic soft tissue sarcoma

medwireNews: Doxorubicin remains the standard of care for patients with metastatic soft tissue sarcoma, researchers say, after the PICASSO III trial failed to show improved survival outcomes with the addition of palifosfamide.

“The observed median PFS [progression-free survival] and overall survival [OS] in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma”, say Christopher Ryan, from Oregon Health & Science University in Portland, USA, and colleagues.

Median PFS was 6.0 months for the 226 patients who were randomly assigned to receive up to six cycles of doxorubicin 75 mg/m2 on day 1 plus palifosfamide 150 mg/m2 on days 1 to 3.

This was comparable to the 5.2 months of PFS achieved by the 221 patients in the phase III trial who were randomly assigned to receive doxorubicin plus placebo, giving a nonsignificant hazard ratio of 0.86.

OS also did not significantly differ between the palifosfamide and placebo treatment arms, at a median of 15.9 versus 16.9 months, the team reports in the Journal of Clinical Oncology.

A quarter of the patients given palifosfamide had to reduce the drug dose and they were also more likely to require a doxorubicin dose reduction than their placebo-treated counterparts, resulting in a slightly lower relative dose density for doxorubicin (94.8 vs 96.5%).

Moreover, combining doxorubicin with palifosfamide increased the rate of grade 3 or 4 side effects, affecting 63.6% of patients versus 50.9% of those given doxorubicin plus placebo. This included a higher rate of febrile neutropenia in the palifosfamide arm (21.4 vs 12.6%) and an “unexpected” case of grade 3 encephalopathy 12 days after the final dose.

Doxorubicin plus palifosfamide was thought to be related or possibly related to two fatalities from cardiac arrest and brain haemorrhage without thrombocytopenia, while the doxorubicin plus placebo regimen was thought associated with five deaths, including three cases from septic shock or sepsis, one from right ventricular failure and another from haemorrhagic shock.

Acknowledging that the study failed to confirm an earlier nonblinded phase II study showing improved PFS with the addition of palifosfamide to doxorubicin, the researchers say the “discrepancy in results underscores the limitations of small, randomized studies, especially in a heterogeneous group of diseases such as soft tissue sarcoma”.

They add that the median OS, of 8 to 14 months, with doxorubicin alone in their study is longer than that previously reported over 3 decades of trials for soft tissue sarcoma, and likely due to improvements in supportive care or histology migration.

“The median PFS of 5.2 months and OS of nearly 17 months with doxorubicin should serve as a reference in the design of future studies in the first-line treatment of metastatic soft tissue sarcoma”, they therefore recommend.


Ryan CW, Merimsky O, Agulnik M, et al. PICASSO III: A phase III, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma. J Clin Oncol 2016; Advance online publication 12 September. doi: 10.1200/JCO.2016.67.6684

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