Pharmacology and Toxicology

Background: Angiosarcomasare rare malignant tumors of vascular origin that represent a therapeutic challenge. In recent times,the combination of metronomic therapies and drug repositioning has been proposed as an effective alternative for cancer patients. We tried to explore such therapies in difficult to treat, metastatic/recurrent, angiosarcoma patients.

Methods: In vitro experiments with transformed endothelial cells were used to identify synergistic interactions between betablocker

propranolol and various chemotherapeutic drugs. This led to exploration of pilot treatment protocol containing oral propranolol along with metronomic therapies. Treatment was delivered for one year followed by oral maintenance till disease progression.

Results: Our data shows that all angiosarcoma tumors express ADRB1 and /or ADRB2 adrenergic receptor genes. Propranolol

strongly synergized with micro-tubular-targeting agent vinblastine, but only showed additive or slight antagonism with drugs routinely used for the treatment of angiosarcoma viz. doxorubicin and paclitaxel. Based on this data a combination treatment was designed using oral propranolol / weekly injectable metronomic vinblastineand methotrexate, given for up-to 1 year, followed by oral maintenance with propranolol/ etoposide/ cyclophosphamide. This regimen gave us 100% response rate in the 14 patients treated with median PFS of 10.6 months and OS of 17.8 months. The toxicity was acceptable with 3 patients having grade 3 or 4 toxicity (1 Thrombocytopenia, 1 diarrhea, 1 febrile neutropenia).

Conclusion: Our data provides strong rationale for the combination of metronomic chemotherapy and propranolol in angiosarcoma which warrants additional studies. It also illustrates the potentialof metronomics to generate innovative, yet inexpensive, targeted therapies for both high-income and low/middle income countries.