Long-Term Follow-up of a Randomized Study of Oral Etoposide versus Fermentatum Pini as Maintenance Therapy in Osteosarcoma Patients in Complete Surgical Remission after Second Relapse.

Background: In relapsed osteosarcoma, the 5-yr postrelapse disease-free survival (PRDFS) rate after the second relapse is <20%. In June 2007, a randomized study was started comparing oral etoposide vs fermentatum Pini (an extract derived from the parasitic plant L., European mistletoe) as maintenance therapy in patients with metastatic osteosarcoma in complete surgical remission after the second relapse. The primary endpoint was the PRDFS rate at 12 months (compared to the historical control rate). This is a long-term updated result. . 10 patients received oral etoposide 50 mg/m daily for 21 days every 28 days for 6 months, and 9 patients received fermentatum Pini 3 times/wk subcutaneously for 1 year. The study closed early in July 2011 due to insufficient recruitment. Lymphocyte subpopulations were analyzed at T0, T3, T6, T9, and T12 months.

Results: On 30 June 2019, at a median follow-up ITT of 83 months (range 3-144 ms), a median PRDFS of 106 ms (2-144) was observed in the arm with 5/9 patients who never relapse vs a PRDFS of 7 months (3-134) in the etoposide arm (all patients in the Etoposide arm relapsed) (hazard ratio HR = 0.287, 95% CI: 0.076-0.884, =0.03). Model forecast 10-yr overall survival rates as 64% in the arm and 33% in the etoposide arm. Lymphocyte subpopulation counts (CD3, CD4, and CD56) showed an increase in the Viscum arm while a decrease was observed in the etoposide arm during treatment.

Conclusions: After 12 years from the start of the trial, the patients in the arm continue to show a considerably longer PRDFS compared to oral etoposide, and a trend for an advantage in OS is evident even if the number of treated patients is too small to draw conclusions. as maintenance treatment after complete surgical remission in relapsed osteosarcoma should be further investigated and compared with other drugs.