Gemcitabine‐induced severe pulmonary toxicity

Abstract

Gemcitabine is a relatively new deoxycytidine analog (2',2'-difluorodeoxycytidine) with structural similarities to cytosine arabinoside (Ara-C). Activity of gemcitabine is demonstrated in the treatment of many solid tumors, like pancreas, ovarian and nonsmall cell lung cancer (NSCLC). Although gemcitabine is considered as a drug with a good safety profile, cases of gemcitabine-induced severe pulmonary toxicity (GISPT) were reported as for Ara-C. We performed a systematic review of reported cases on the GISPT. Twenty-nine clinical trials especially interesting NSCLC patients (21) and 21 reported cases recording 40 patients were analyzed. The incidence of the GISPT varies from 0 to 5%. The clinical presentation is a subacute clinical syndrome and is frequently nonspecific. The predominant radiographic pattern on chest X-ray are reticulo-nodular interstitial infiltrates. It was postulated that the physio-pathological mechanism of the GISPT was an inflammatory reaction of the alveolar capillary wall cytokine-mediated, which created an abnormal permeability of its membrane. After the differential diagnosis were ruled out, the discontinuation of the drug and the early initiation of steroids and diuretics are the most frequently performed treatments. Under these conditions, the outcome was favorable in a delay of few days generally for a majority of patients but 20% of patients died. Some risk factors, as a previous pulmonary disease or a previous thoracic irradiation, for the occurrence of the GISPT were proposed. GISPT is rare but sometimes fatal. Its a necessity to increase awareness about it to enhanced an early and suitable management of patients developing such a toxicity after gemcitabine administration.

Gemcitabine Pulmonary Toxicity in Ovarian Cancer

“…It is unclear whether alkaline phosphatase is related to lung toxicity or is a coincidental effect of gemcitabine, though they seemed to occur simultaneously in this patient. In a recent review, the onset of toxicity occurred at a median of the second cycle, though it also occurred after the first administration or several cycles thereafter [8].…”

“…However, a few reports have described gemcitabine-induced lung toxicity [1][2][3][4][5][6][7]. Recently, this toxicity was reported in patients with ovarian cancer [2,8,9]. Although up to 23% of patients treated with gemcitabine may develop dyspnea, a small fraction of patients may develop severe dyspnea, diffuse alveolar damage, acute respiratory distress syndrome, interstitial pneumonitis, or noncardiogenic pulmonary edema requiring steroid therapy [2, 4, 5, 8 -10].…”

“…The outcome of Gemzar lung varies from recovery to death [2][3][4][5]9]. In one review, the mortality rate was 20% [8]. The age profile of gemcitabine pulmonary toxicity, described in adults 31-85 years old with the majority of patients aged 50 -60 years, may reflect the predominance of cancer diagnoses during these decades.…”

Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis

“…[26][27][28] To avoid severe toxicity and improve survival, GMT-based therapy is often used in combination with other agents. 6,[20][21][22][23][24][25][33][34][35][36] We have previously shown that TMX, as a CaM antagonist, induces apoptosis in human cholangiocarcinoma cells, which lack ERs. [10][11][12][13] We reported that TMX-induced apoptosis is partially dependent on inhibition of pAKT and FLIP expression, as well as activation of caspases 8, 10, 9, and 3.…”

“…32 Low dose of GMT is preferred to avoid severe toxicity, especially pulmonary toxicity. [33][34][35][36] Hence, combination therapies with GMT plus a variety of chemotherapeutic agents have been employed to minimize toxicity and maximize therapeutic efficacy. Currently, GMT combined with chemicals like leucovorin, 5-fluorouracil, capecitabine, and platinum agents have shown enhanced therapeutic effects in cholangiocarcinoma.…”