According to recent estimates, by 2025 the prevalence of cancer is expected to soar by 45% in developed countries. Cancer is the second cause of death worldwide following cardiovascular diseases. More than one million cases of gastric cardia and 450,000 cases of esophageal cancers are being diagnosed annually, which are the seventh and eighth most prevalent cancers, respectively [1,2,3,4]. In Iran, according to the recent predictions, the incidence of cancer is expected to increase by 42.6% until 2025. In other words, the number of new cancer cases is predicted to rise from 112,000 cases registered in 2016 to an estimated 160,000 cases in 2025. Meanwhile, in 2016, breast, colorectal and stomach cancers were the most commonly diagnosed cancers, being predicted to remain the top three cancer types in 2025 [5].

Chemo-radiotherapy with or without surgery is an approved and favored treatment strategy in gastric cardia and esophageal cancers. Esophagitis and aggravation of transient dysphagia is witnessed in approximately 75% of patients who undergo chemoradiotherapy. Besides, they may experience early acute complications such as dermatitis, fatigue, weight loss, nausea and vomiting, as well as hematological complications like lymphopenia, granulocytopenia, thrombocytopenia and finally anemia [6].

Irradiation-induced dose-dependent decrease occurs in all hematopoietic cell lineage. Reduction in the number of lymphocytes, granulocytes, and red blood cells occurs in hours, days, and weeks after the initiation of treatment, respectively [7]. Through studying murine models, the effects of irradiation on hematopoiesis have thoroughly been investigated, namely it causes oxidative damage, negatively affects DNA damage repair and cell proliferation, and promotes cell senescence [8]. Among them, leukocytes, especially lymphocytes, are the most radio-sensitive cells [7, 8]. Moreover, several studies have demonstrated that the drop in the number of lymphocytes remains for years following the radiotherapy [9,10,11], which has a significant impact on reducing the prognosis of patients with cancer [12,13,14].

The importance of the adverse consequences of radiotherapy particularly the hematological complications becomes more prominent with acknowledging the fact that radiotherapy is widely used all over the world for either palliative or curative purposes. Of nearly 10.9 million people who are diagnosed with cancer annually, radiation therapy is given to about 60%, among them 40% are meant for curative treatment [15].

Effective and timely management of radiotherapy complications should be taken seriously. For radiation oncologists, identifying an efficient and non-toxic radio-protective agent has always been essential. Radio-protective agents are utilized in order to prevent or reduce cellular damage due to ionizing radiation. They are often antioxidants that must be administered concomitantly or prior to the treatment [15].

Sulfur compounds such as amifostine are the first compounds that have been evaluated as radio-protective agents. Evidence suggests that amifostine is a potent and systemically effective radioprotector when it is administered in high doses. However, it shows toxicity at the high doses required for radioprotection that pertains to survival benefits. Its severe side effects (e.g. nausea, vomiting, and hypotension), along with the non-oral route, and the need for blood pressure monitoring during injection have hindered its use. Therefore, there is still a considerable need for an effective agent with minor side effects [16].

It has been shown that H2 receptor antagonists such as cimetidine and famotidine have radioprotective effects. Famotidine has been known as a strong agent to reduce radiation-induced apoptosis, as well as lipid peroxidation, DNA damage, chromosomal aberrations, micronuclei formation, and lethality [17].

Existing evidence confirms that famotidine has been a promising agent in protecting leukocytes from radiation-induced apoptosis [18]. It has also been demonstrated that famotidine can lead to a significant drop in radiation-induced lymphocytopenia [19]. Yet, there is scarce evidence supporting the use of famotidine as a redioprotective drug. Studies especially clinical trials in the field of radioprotective agents have been conducted inadequately. Addressing this issue can substantially contribute to enhancing the tolerance of radiation therapy, increasing life expectancy, and improving the prognosis of cancer. The present study is designed to examine famotidine as a radioprotective drug in reducing the hematological complications of radiation therapy among a population of patients with cardia and esophageal cancers.