Pemetrexed-Induced Fluid Retention
Authors: Diogo Assed Bastos, Aknar Calabrich, Artur Katz
Journal: Journal of Thoracic Oncology (2010)

Despite the favorable toxicity and safety profiles of pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN), several adverse events have been reported, including blood and lymphatic system disorders, gastrointestinal disorders, and general disorders.1Hanna N Shepherd FA Fossella FW et al.Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.J Clin Oncol. 2004; 22: 1589-1597Crossref PubMed Scopus (2295) Google Scholar, 2Russo F Bearz A Pampaloni G Pemetrexed single agent chemotherapy in previously treated patients with locally advanced or metastatic non-small cell lung cancer.BMC Cancer. 2008; 8: 216Crossref PubMed Scopus (27) Google Scholar, 3Pujol JL Paul S Chouaki N et al.Survival without common toxicity criteria grade 3/4 toxicity for pemetrexed compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): a risk-benefit analysis.J Thorac Oncol. 2007; 2: 397-401Crossref PubMed Scopus (63) Google Scholar In this letter, we describe a case series consisting of seven patients who developed clinically significant fluid retention, an uncommon adverse effect associated with the use of pemetrexed. All patients have received vitamin supplementation and were pretreated with corticosteroids as indicated in the package insert (Table 1).TABLE 1Patients Characteristics CaseAge (yr)SexComorbiditiesRegimenNo. of Cycles at Edema OnsetEdema LocalizationGradeaCommon Terminology Criteria for Adverse Events v 3.0 (CTCAE).Edema TreatmentContinued on PemetrexedActual Treatment 161FNoneCarboplatin and pemetrexed (first line)7Eyelid and ankleINoYesPemetrexed maintenance 239FNonePemetrexed (second line)13Generalized (facial, peripheral, and pleural effusion)IIYesYesPemetrexed 370MHypertension, chronic obstructive pulmonary disease, and pulmonary embolismCarboplatin and pemetrexed (second line)13PeripheralIIYesYesPemetrexed maintenance 463MNoneCarboplatin, pemetrexed, and bevacizumab (first line)14Generalized (facial, peripheral, and pleural effusion)IIIYesNoErlotinib and bevacizumab 547FDepressionPemetrexed and bevacizumab (third line)16FacialINoYesPemetrexed and bevacizumab 674MDiabetesPemetrexed and bevacizumab (second line)6PeripheralIIYesNo— 749FNonePemetrexed and bevacizumab (second line)8AnkleINoYesPemetrexed and bevacizumaba Common Terminology Criteria for Adverse Events v 3.0 (CTCAE). Open table in a new tab Other causes of edema were excluded, and all patients had normal echocardiogram, normal levels of B-type natriuretic peptide and albumin, normal renal, hepatic, and thyroid function tests, and no significant proteinuria. Most patients presented with mild-to-moderate edema, mainly in periorbital area, as illustrated in Figure 1 (case 1). Of the seven cases, only one patient (case 4) developed grade 3 refractory edema with symptomatic bilateral effusion. A bilateral thoracocentesis was necessary for symptom relief, and the pleural effusion analysis was consistent with an exudate with no malignant cells and negative cultures. There was complete disappearance of generalized edema and bilateral pleural effusion after discontinuation of pemetrexed treatment. Another patient (case 6) also had complete resolution of the edema after pemetrexed was discontinued because of disease progression. All other cases were managed with observation only or salt restriction and diuretics, with limited control of this side effect. Because of sustained partial responses and disease control, treatment with pemetrexed was continued in all but one patient, which was described above, despite the incomplete control of this problem. Pemetrexed-associated peripheral and eyelid edema has been rarely reported, with an estimated incidence of 1% in clinical trails.1Hanna N Shepherd FA Fossella FW et al.Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.J Clin Oncol. 2004; 22: 1589-1597Crossref PubMed Scopus (2295) Google Scholar, 4Kurata T Tamura K Okamoto I et al.Pemetrexed-induced edema of the eyelid.Lung Cancer. 2006; 54: 241-242Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar To our knowledge, there were no severe cases reported with need for treatment discontinuation until now. The mechanism involved in the development of fluid retention and consequent edema is unknown, but may be because of capillary leakage syndrome.4Kurata T Tamura K Okamoto I et al.Pemetrexed-induced edema of the eyelid.Lung Cancer. 2006; 54: 241-242Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Now that pemetrexed has demonstrated efficacy in the first-line setting and is an option as maintenance or early second-line therapy, more patients will be exposed to this agent, and therefore more individuals will potentially develop this treatment-related adverse effect. Therefore, we believe it is important to report this unusual adverse event and to understand its pathophysiology to attempt to develop strategies to avoid and manage this uncommon side effect. The authors thank the patients for their explicit consent for sharing their clinical information in this report, especially Mrs. ANPC for allowing us to use her photograph for illustration. Diogo Assed Bastos, MD Aknar Calabrich, MD Artur Katz, MD Oncology Center Sírio Libanês Hospital São Paulo, Brazil