Lay Abstract
Sorafenib is one of the most commonly used drugs in people with desmoid. Other than desmoid, it is used in metastatic (widespread) cancers like kidney cancer and thyroid cancers. The duration of treatment in these cancers is limited and also given the short life expectancy in these cancers, long term side effects of sorafenib on different body functions is not well known.
Other than this the current duration of treatment in desmoid is not known and is continued indefinitely. In smaller studies, sorafenib has been shown to affect thinking, heart functioning, fertility even with limited duration. Through this study we want to see how sorafenib affects these organs systematically. We will assess cardiac functions, vascular functions, cognitive functions and hormonal function and see the trend during the first year. It will be a stepping stone for any intervention that can reduce the chances of long term complications.
We will try to continue this study for 3 years.
Scientific Abstract
So far, sorafenib has been used in various advanced cancers with limited life expectancy and long term side effects involving cognition, cardiovascular and reproductive functions have rarely been looked at. Currently, the duration of sorafenib therapy in desmoid is not evidence based and it is continued indefinitely. In a study by Mulder et al, comprised of patients with GIST and RCC, the effects of VEGF inhibitors was larger on learning, memory and executive functions as compared to patients not on these drugs. (1). So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning in desmoid. Once the cognition function is delineated then further research can be done on using neuroprotective strategies.(2)
In a meta analysis by Dai et al, VEGFR inhibitors are also significantly associated with hyperlipidemia. Similarly, it has been recently shown that sorafenib acutely affects cardiac contractility by reducing S16 PLN phosphorylation, leading to reduced SR calcium content, CaT amplitude, and slowed cytosolic calcium removal (3). Coronary artery disease has been also been described in patients on sorafenib especially associated with patients with preexisting cardiovascular comorbidity.(4)
Though menstrual abnormalities are not reported commonly with TKIs but in our unpublished data (ongoing study), it is one of the most common complaints on long term use. In a report by Sanctis et al, an 18 year old girl developed reversible ovarian insufficiency on pazopanib (5). . There is only one study of 17 women with desmoid tumor addressing fertility preservation using IVF, of which only one was on Sorafenib therapy. The study reported very poor yield of oocytes in her first IVF cycle (2.7 (±1.3) which improved significantly after stopping Sorafenib 13.2 (±3.3) (P = 0.02). (6)
We have devised comprehensive screening strategies at various time points as shown in the table below with the budget justification. We want this to be a recurring project for the next 3 years. It will be a prospective study which will be enrolling patients with fibromatosis more than 18 years old and have been started on sorafenib within 2-3 months. A total of 50 patients will be recruited in around 1 year duration.
Methodology
It will be a prospective study which will be enrolling patients with fibromatosis more than 18 years old and are preferably newly diagnosed (drug naïve) or have been started on sorafenib within 2-3 months. A total of 50 patients will be recruited in around 1 year duration.
