Chemotherapy-induced pulmonary hypertension: Role of alkylating agents

Abstract

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

“…W przeciwieństwie do innych form PAH, ta jest często odwracalna po przerwaniu podawania leku lub zamianie na inny TKI, taki jak nilotinib. Ostatnio zwrócono uwagę na to, że cyklofosfamid i inne leki alkilujące mogą przyczyniać się do rozwoju choroby zarostowej żył płucnych [207], która zajmuje głównie małe żyłki i jest najcięższą postacią nadciśnienia płucnego, w przypadku której nie ma żadnej skutecznej farmakoterapii.…”

Pulmonary hypertension

“…Of interest is the recent study by PERROS et al [6] showing not only that mitomycin is a risk factor for the development of PVOD, but also that mitomycin induces pulmonary vascular disease in rats that resembles the pathological features of PVOD. This finding not only offers a representative animal model to study the disease but also sheds new light on the possible role of alkylating chemotherapy on the development of pulmonary hypertension [7]. New associations between drugs and disease were not only made in PVOD; in PAH, a possible relationship between a drug and the disease also was found.…”

Insights into etiological factors of pulmonary hypertension in cancer patients

“…A study of animal models demonstrated a direct relationship between exposure to alkylating agents especially cyclophosphamide and development of pulmonary venous remodelling leading to PVOD and PH. The study also showed a beneficial role for the cytoprotective agents mesna and amifostine to protect pulmonary vasculature from the harmful effects of chemotherapy [45].…”