Rare Case of Reversible Pulmonary Arterial Hypertension Secondary to Cyclophosphamide and Doxorubicin Chemotherapy

Abstract

Pulmonary arterial hypertension (PAH), characterized as a resting mean pulmonary artery pressure greater than 25 mmHg, is due to the narrowing of the pulmonary arteries, which can be idiopathic, inherited, or drug-related. Alkylating agents, including cyclophosphamide, are a risk factor for developing the pulmonary veno-occlusive disease. Drug-induced PAH is extremely rare. A 59-year-old female with newly diagnosed invasive ductal carcinoma of the right breast and high-grade ductal carcinoma in situ of the left breast was initiated treatment with doxorubicin and cyclophosphamide. About one week after receiving the first cycle, the patient developed worsening lower extremity edema and shortness of breath. She was then hospitalized, and a transthoracic echocardiogram and coronary angiogram revealed PAH. The team then changed the breast cancer treatment regimen to Taxol and carboplatin, and PAH was resolved in a follow-up echocardiogram after five months. This report has described the first case of PAH directly related to cyclophosphamide and doxorubicin. It is imperative to promptly recognize this rare but important sideeffect as early diagnosis and response can potentially reverse the disease progression.

Pulmonary arterial hypertension in an 80-year-old man with long-term use of cyclophosphamide

“…To date, there have been approximately only 20 case reports, which have shown possible associations between cyclophosphamide use and PAH [ [3] , [4] , [5] , [6] , [7] , [8] ]. However, only limited data were documented in these reports, and the association between the use of cyclophosphamide and the development of PAH was not necessarily evident.…”

“…A systematic review reported by Benoit et al, in 2015 reviewed cases of chemotherapy-induced PVOD from the French PH network and reported that cyclophosphamide was used in 16 of the 37 cases they identified [ 4 ]. Aside from these 16 cases, there have been four other cases, in which PH developed following the use of cyclophosphamide [ 3 , 5 , 6 ]. Notably, in all these cases, multiple chemotherapeutic agents were used simultaneously, and ten patients underwent bone marrow transplantation; thus, the association between the use of cyclophosphamide and the development of PAH was not clearly elucidated [ [3] , [4] , [5] , [6] ].…”

“…Aside from these 16 cases, there have been four other cases, in which PH developed following the use of cyclophosphamide [ 3 , 5 , 6 ]. Notably, in all these cases, multiple chemotherapeutic agents were used simultaneously, and ten patients underwent bone marrow transplantation; thus, the association between the use of cyclophosphamide and the development of PAH was not clearly elucidated [ [3] , [4] , [5] , [6] ]. In contrast to these previous reports, the only factor that could have induced PAH in this case was the use of cyclophosphamide.…”

“…It is known to induce cardiovascular adverse events in some cases and is included in pharmacologic agents with possible associations with PAH [ 2 ]. To date, several publications have reported cases of patients who developed PH associated with the use of cyclophosphamide [ [3] , [4] , [5] , [6] , [7] , [8] ]. However, all these cases involved factors other than cyclophosphamide use that might have contributed to the development of PH; some were diagnosed with PH without right heart catheterization (RHC), or with limited clinical and hemodynamic data [ [3] , [4] , [5] , [6] , [7] , [8] ].…”

Right Ventricular Dysfunction in the Cancer Patient

“…Evidence suggests that cyclophosphamide and its metabolites cause peroxidation of cell membrane lipids. 28 A systematic review of the role of alkylating agents in the development of pulmonary hypertension, published in 2015 established that these compounds, including cyclophosphamide, are a risk factor for pulmonary veno -occlusive disease. In experimental models, cyclophosphamide exposure leads to venous remodeling, which, in turn, leads to the development of pulmonary hypertension.…”