Gemcitabine, chemotherapy for solid tumors, may lead to PAH
Study urges 'vigilance' in monitoring cancer patients using this treatment
Gemcitabine, a chemotherapy given to treat solid cancers, may drive the onset of pulmonary arterial hypertension (PAH) in patients or worsen existing PAH, a recent study reports.
Stopping treatment with gemcitabine, with or without a subsequent PAH-approved treatment, led to clinical improvement or disease stabilization for a majority of nine patients in France.
“The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained [shortness of breath],” the researchers wrote.
They suggested that “gemcitabine chemotherapy could be added to the list of drug treatments potentially linked to the onset of PH, thereby heightening vigilance during its usage.”
Gemcitabine has known heart and lung toxicities, but PAH rarely reported
The study, “Characteristics and outcomes of gemcitabine-associated pulmonary hypertension,” was published in the European Respiratory Journal.
PAH is a form of pulmonary hypertension (PH) characterized by the narrowing of the blood vessels that transport blood from the heart to the lungs. As a result, the heart’s right ventricle needs to work harder to pump blood, becoming gradually enlarged and weakened.
The disease can be associated with various conditions, such as connective tissue diseases or congenital heart disease, as well as by exposure to certain drugs, including chemotherapies or amphetamines.
PAH caused by exposure to gemcitabine, a chemotherapy known to have cardiac and lung toxicities, however, has rarely been reported. The specific mechanisms likely to trigger PAH are not well understood, the researchers, all in France, wrote.
The team analyzed data covering nine people with gemcitabine-associated PAH identified through the French PH Registry. Eight were diagnosed with PAH induced by gemcitabine exposure, and one with a previous PAH diagnosis showed evidence of disease worsening with the chemotherapy’s use. In all patients, a PAH diagnosis was confirmed by right heart catheterization.
Seven of the patients, all men with a median age at diagnosis of 78, were former smokers, while two had never smoked.
Five had mild-to-moderate chronic obstructive pulmonary disease and one had and interstitial lung disease, a condition characterized by the accumulation of scar tissue in the lungs, but no “respiratory impairment prior to exposure to gemcitabine,” the researchers noted.
None of the men “had been exposed to organic solvents or drugs known or suspected of inducing PAH,” they added.
Nine patients given the chemotherapy for a median of 7 months
Gemcitabine was used to treat nonsmall cell lung cancer in five patients, pancreatic cancer in two others, and urothelial carcinoma (a common type of bladder cancer) in the remaining two men. Patients received a median of 16 gemcitabine injections, usually at a dose of 1 g per square meter of body surface area.
The median time since gemcitabine initiation to PH diagnosis was seven months, with initial symptoms appearing one month earlier. At the time PH was diagnosed, five patients had responded to the treatment, three showed cancer progression, and one had stable disease.
Mean pulmonary artery pressure (mPAP) was high at 40 mmHg, whereas elevated pulmonary vascular resistance — a measure of the internal resistance to blood flow within lung arteries — also was high at 6.3 Wood units. Other blood flow assessments were in line with severe PAH.
Gemcitabine treatment stopped for all nine patients after PH was diagnosed. Three men showed a “spontaneous clinical improvement” and two survived without any treatment for PAH. Five patients were given a stand-alone treatment as monotherapy. Two of them experienced clinical improvement or stabilization, while the disease worsened in the other three.
“The notable clinical and [blood flow] improvement observed after the discontinuation of gemcitabine strongly suggests the role of this drug in the onset of PH,” the researchers wrote.
65% of 109 cases of PH related to gemcitabine’s use reported in US
Five of these nine patients died after a median follow-up of 18 months (1.5 years), with known causes including acute right heart failure in two men and cancer progression in two others. This equated to a median overall survival since PH diagnosis of 18 months, with a survival rate of 77% at one year, and 44% at two years.
A search of the World Health Organization pharmacovigilance database in June 2023 identified 109 cases reporting at least one adverse event related to PH and gemcitabine use. Almost two-thirds of the cases were in the U.S. (65.1%), followed by France (13.8%) and Germany (10.1%).
Among 22 patients with a reported gemcitabine discontinuation, 12 experienced an easing of PH symptoms, further suggesting improvements after stopping treatment.
“It is thus crucial to inform physicians, urging them to remain vigilant for symptoms like [shortness of breath] following the administration of this type of chemotherapy. They should consider the possibility of PH in patients treated with gemcitabine … and propose early detection,” the researchers wrote.
About the Author
