Efficacy and Safety of High Dose Aprepitant Treatment in Patients With Advanced Non-Small Cell Lung Cancer
Lung cancer is one of the most common causes of cancer death in worldwide. It is projected that the vast majority, approximately 80% -85% of all lung cancer diagnosis is Non-Small Cell Lung Cancer (NSCLC). Although there are significant improvements in the treatment of Lung Cancer in recent years, there is still an unmet medical need for a specific population which have advanced NSCLC and mostly is refractory to existing treatments. NK-1 antagonists are generally safe and well-tolerated drugs and approved for the treatment of chemotherapy induced vomiting and nausea. However, the recent findings in preclinical studies and preliminary results of some case reports have suggested that their potential in cancer treatment may not be limited to only antiemetic effects. In addition to the role of NK-1 pathway in emesis, the neuropeptide substance P (SP) binds to Neurokinin-1(NK-1) receptor and this binding regulates the carcinogenic cell proliferation, exerts an antiapoptotic effect, stimulates cell migration that leads to invasion and metastasis of tumor cells and lastly stimulates neoangiogenesis via endothelial cell proliferation. In this regard, the antitumoral effects of NK-1 antagonists against different types of cancer are a leading area of research interest and need for further investigation. Currently, there are three NK-1 receptor antagonists approved by health authorities: Aprepitant (Emend), its pro-drug, fosaprepitant (Ivemend) and rolapitant (Varubi). All of these drugs are non-peptid NK antagonists and have lipophilic properties. Therefore, they are not degraded by peptidase and can cross the blood-brain barrier (4). In addition to the potential effects of NK-1 antagonists in tumor area, their penetration to central nervous system may also prevent from or reduce the brain metastasis. The long term use of aprepitant as off-label is relatively common. In several case reports, long term use of aprepitant, up to 18 months, was successfully demonstrated in the treatment of refractory nausea and vomiting due to gastroparesis or other unexplained reasons. Additionally, in a very recent publication, it was reported that for the nausea and vomiting associated gastroparesis, long-term off label use of aprepitant was successfully received and well tolerated by three children (5 to 19 month-old) in the course of allogenic hematopoietic stem cell transplantation. In the light of findings in preclinical studies, the antitumor effects of NK-1 antagonists are dose-dependent and the higher doses than approved antiemetic effective dose are need to achieve the antitumor activity. For aprepitant which will be used in present study, it has been recommended >20 mg/kg/day and prolonged use for antitumor activity. In a case report, prolonged use of standard aprepitant dose in a patient with metastatic breast cancer, had resulted with a reduction in CA153 tumor marker levels. In another recently published case report, a patient with lung cancer was treated with combination of aprepitant (1140 mg/day) and radiotherapy for 45 days, it has been reported that the tumor massed had disappeared without any side effect related to aprepitant treatment. It is fact that the evidence is not clear yet and further investigation in clinical trial settings is still needed for the evaluation of the efficacy and safety of high doses and long-term use of aprepitant, especially when administered alone to determine its own effect.
Start: March 2021
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