A Artinyan

A Hilbig

EM O’Reilly

F Barlési

FH Galvão

H Ueno

Hirokazu Noshiro

J Allen

JL Abbruzzese

Kazutoshi Komiya

Kenji Kitahara

N Gupta

Naoko Sueoka-Aragane

PM Boiselle

Shinya Kimura

T Hagio

T Higenbottam

T Johkoh

Takashi Sugioka

Tomomi Yakabe

YH Kim

World Journal of Surgical Oncology

Crossref

WORLD JOURNAL OF SURGICAL ONCOLOGY Yakabe et al. World Journal of Surgical Oncology 2013, 11:167http://www.wjso.com/content/11/1/167CASE REPORT Open AccessSevere eosinophilic pneumonia presenting duringgemcitabine adjuvant chemotherapyTomomi Yakabe1,2*, Kenji Kitahara2, Kazutoshi Komiya3, Naoko Sueoka-Aragane3, Shinya Kimura3,Takashi Sugioka1 and Hirokazu Noshiro2AbstractGemcitabine is widely accepted as the standard treatment for pancreatic cancer, but it can cause unpredictableside effects. Acute respiratory distress syndrome is a rare complication with gemcitabine, but is sometimes fatal. Wedescribe a cured case of acute, severe gemcitabine-induced pulmonary toxicity. The patient was a 76-year-old manwith pancreatic cancer who was receiving adjuvant gemcitabine chemotherapy after surgery. The patient receivedgemcitabine 1,000 mg/m2 on days 1, 8, and 15 for three 4-week cycles, with intervals of 1 week. He developedsevere general fatigue on day 1 of the third cycle. Computed tomography showed diffuse ground-glass opacitywith pleural effusion. There was no increase in β-D-glucan, and cytomegalovirus antigenemia assays were negative.No bacteria or acid-fast bacilli were found. The number of eosinophils in bronchoalveolar lavage fluid wasincreased. Considering these data, we diagnosed eosinophilic pneumonia induced by gemcitabine. The patient wasimmediately treated with a steroid and neutrophil elastase inhibitor under respiratory supportive therapy. After 4weeks, his pulmonary symptoms were markedly improved. Physicians should be cognizant of the possibleassociation of serious pulmonary toxicity with gemcitabine treatment. A delay in diagnosis and treatment couldlead to a fatal outcome.Keywords: Pancreatic cancer, Gemcitabine, Adjuvant chemotherapy, Eosinophilic pneumonia, Acute lung injury,Adverse event, Pulmonary toxicityBackgroundSurgery is considered to be only curative option forpatients with resectable pancreatic cancer. However,adjuvant therapy is considered to improve the surgicaloutcome because there is the high recurrence rate of thedisease even after curative resection [1-4]. Gemcitabine(2’,2’-difluoro-s’-deoxycytidine) is widely accepted as thestandard treatment for pancreatic cancer.Two recent randomized phase III trials of adjuvantchemotherapy have been conducted in patients withresected pancreatic cancer. The CONKO-001 studycomparing surgery followed by gemcitabine with surgeryalone suggested that adjuvant gemcitabine did indeedcontribute to prolongation of disease-free survival, al-though overall survival did not differ significantly* Correspondence: kashiwad@cc.saga-u.ac.jp1Department of Community Medical Support Institute, Saga University, Saga,Japan2Department of Surgery, Saga University Faculty of Medicine, Saga, JapanFull list of author information is available at the end of the article© 2013 Yakabe et al.; licensee BioMed CentralCommons Attribution License (http://creativecreproduction in any medium, provided the orbetween the two groups [1]. The JSAP-02 study under-taken in Japan showed similar results [5], differing only inthe planned number of gemcitabine cycles: three cycles ofgemcitabine were used in JSAP-02 in contrast to sixcycles in CONKO-001. The most common side effect ofgemcitabine is myelosuppression. Severe pulmonarytoxicity as a side effect is relatively rare, with a reportedincidence of between 0 and 5%, but 20% of patients withsevere pulmonary toxicity died [6].We describe a rare case of potentially fatal severeeosinophilic pneumonia induced by gemcitabine, whichwas successfully treated.Case presentationThe patient was a 76-year-old manreceiving gemcitabinechemotherapy for stage IIIA pancreatic cancer afterundergoing subtotal stomach-preserving pancreaticodu-odenectomy for a tubular adenocarcinoma in the pan-creas. Six weeks later, the patients was started ongemcitabine (Gemzar®; Eli Lilly, Indianapolis, IN, USA) atLtd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.Yakabe et al. World Journal of Surgical Oncology 2013, 11:167 Page 2 of 4http://www.wjso.com/content/11/1/167a dose of 1000 mg/m2 over 30 min on days 1, 8, and 15every 4 weeks. This 4-week cycle was repeated for threecycles, with a 1-week interval between them, based on theprotocol used in the JSAP-02 study [5].The patient developed severe general fatigue on day 1of the third cycle. Arterial blood gas analysis showedhypoxemia (PaO2 62 Torr with 8 l/min of oxygen by facemask). His white blood cell count was 17.1 × 109/l with80.7% neutrophils and 1.0% eosinophils. He reportedgeneral fatigue and dyspnea but no cough.On physical examination, the patient had negligiblecrackles and poor inspiration in both lungs. Computedtomography (CT) showed pleural effusion in both sidesof the thorax, and diffuse ground-glass opacity, thick-ened septal line,s and diffuse reticular opacity in bothlungs (Figure 1). There was no increase in β-D-glucan,and cytomegalovirus antigenemia assays were negative.No bacteria or acid-fast bacilli were found. Pleural fluidcytology was also negative for cancer cells. Laboratorystudies revealed that the patient’s lactate dehydrogenaselevel was 253 U/l, KL-6 was 298 U/ml, and SP-D was107 ng/ml. Antibiotics and sivelestat sodium hydratehad been started on admission, under a working diagno-sis of acute lung injury due to infection. However, thepatient’s respiratory status did not improve. Bronchoal-veolar lavage (BAL) was performed for further differen-tial diagnosis. The percentage of eosinophils in the BALfluid was raised (56%), strongly suggesting a diagnosisof gemcitabine-induced acute eosinophilic pneumonia.The patient was treated with methylprednisolone 1000mg/day and sivelestat sodium hydrate for 3 days, withmethylprednisolone 40 mg/day for a further 11 days,and then started on bi-level positive airway pressure(BiPAP Vision®; Philips International, Amsterdam, TheNetherlands) by face mask to provide non-invasiveFigure 1 Chest computed tomography on admission. Bilateralpleural effusion and diffuse ground-glass opacity was apparent, andthickened septal lines and diffuse reticular opacity were evident inboth lungs.pressure support at 5 cm H20. After 4 weeks, there wasmarked improvement in the pulmonary symptoms andCT findings (Figure 2).Gemcitabine is relatively well tolerated, and myelosup-pression is generally the dose-limiting toxicity; pulmonarytoxicity with gemcitabine is relatively uncommon. Theincidence of grade 4 lung toxicity ranges from 0.06%, asreported by an industry study based on commercial expos-ure, to 8%, as reported in several case study reviews, andthe mortality rate is 20% [7,8]. In addition, gemcitabine-induced eosinophilic pneumonia has been reported previ-ously [9,10]. Thus, diagnosis of drug-induced pneumoniahas now become more important for patients with cancer.We also investigated the prevalence of drug-inducedpneumonia in patients with pancreatic cancer or biliarytract cancer. From data collected on 92 patients treatedwith gemcitabine alone for pancreatic or biliary tractcancer between January 2007 and December 2010 at ourinstitution (Table 1), the common reasons for treatmentdelay were myelotoxic effects, infection, and emesis. Dis-continuation because of grade 3 or 4 myelosuppression,hepatobiliary disorder, and malaise occurred in 4 (4.0%) of100 events. Drug-induced pneumonia as the main reasonfor discontinuation accounted for two of six cases (33.3%)in whom gemcitabine was discontinued, suggesting thatgemcitabine-induced pneumonia has significant morbidityand mortality.Pulmonary eosinophilic infiltrates are a heterogeneousgroup of disorders characterized by the presence of eosin-ophils in the lungs, as detected by BAL or tissue biopsy,with or without blood eosinophilia. Pulmonary infiltrates,characterized by foci of air-space consolidation andfocal ground-glass opacity, can be seen in pulmonaryeosinophilia of all causes [11]. The findings from CTand careful clinical evaluation must correspond in orderFigure 2 Chest computed tomography at 4 weeks after startingtreatment. The ground-glass opacity in both lungs disappearedafter discontinuation of gemcitabine and initiation of corticosteroidsand pulmonary support.Table 1 Reasons for delay or discontinuationin patientswho received gemcitabine systemic chemotherapyNo. of patients (%)Non-hematological,n (%)Treatment delay,n = 94aDiscontinuation ofgemcitabine, n = 6Vomiting 5 (5.3) 0Infection 10 (10.6) 0Drug-inducedpneumonia0 2 (33.3)Diarrhea 2 (2.1) 0Malaise 4 (4.3) 1 (16.7)Patient’s wish 3 (3.2) 0Hematological, n (%)Neutrophil countdecreased36 (38.3) 0Anemia 7 (7.4) 1 (16.7)Platelet countdecreased15 (16.0) 1 (16.7)AST or ALTincreased4 (4.3) 0Blood bilirubinincreased5 (5.3) 1 (16.7)Creatinineincreased1 (1.1) 0Hypoalbuminemia 2 (2.1) 0Abbreviations: ALT, Alanine aminotransferase; AST, Aspartate aminotransferase.aTotal exceeds 92 because of the duplication of patients.Yakabe et al. World Journal of Surgical Oncology 2013, 11:167 Page 3 of 4http://www.wjso.com/content/11/1/167for a definitive diagnosis to be made. BAL is the princi-pal method of confirming the diagnosis of acute eosino-philic pneumonia. In such cases, eosinophils accountfor more than 25% of the cells in the BAL fluid [12]. Inthe present case, eosinophils showed an increase to 56%on BAL analysis, and we ultimately used this finding toreach the diagnosis of eosinophilic pneumonia.Once the diagnosis has been made, the most commontreatment involves stopping gemcitabine and startinghigh-dose steroids such as hydrocortisone, methylprednis-olone, and dexamethasone, which are then tapered overthe course of several weeks alongside oxygen supplemen-tation. In the present case, treatment was started usingsivelestat sodium hydrate (ONO-5046), a neutrophil elas-tase inhibitor developed in Japan. Neutrophil elastase is aprotease produced by inflammatory cells, and its inhib-ition is associated with the prevention of acute lung injury(ALI) in animal models [13]. It has been suggested thatthe physiopathological mechanism of drug-induced ALI isa cytokine-mediated inflammatory reaction of the alveolarcapillary wall [14]. Although the importance of leukocyteelastase relative to other proteases in the pathogenesis oflung injury remains uncertain, we selected this drug onthe expectation of beneficial effects of elastase inhibitionfor drug-induced ALI.ConclusionWe emphasize that physicians must be cognizant that ofthe possible association of serious pulmonary toxicitywith gemcitabine treatment. A delay in diagnosis andtreatment of gemcitabine-induced severe eosinophilicpneumonia could lead to a fatal outcome.ConsentWritten informed consent was obtained from the patient’snext of kin for publication of this Case report and anyaccompanying images. A copy of the written consent isavailable for review by the Editor-in-Chief of thisjournal.AbbreviationsALI: Acute lung injury; ALT: Alanine aminotransferase; AST: Aspartateaminotransferase; BAL: Bronchoalveolar lavage; CT: Computed tomography;KL-6: Krebs von den Lungen-6; SP-D: Surfactant, pulmonary-associatedprotein D.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsTY drafted the manuscript and made revisions. KK performed the surgery. KKand NA participated in the medical treatment. SK and TS helped to draft themanuscript. HN was lead surgeon and reviewed the manuscript. All authorsread and approved the final manuscript.Author details1Department of Community Medical Support Institute, Saga University, Saga,Japan. 2Department of Surgery, Saga University Faculty of Medicine, Saga,Japan. 3Division of Hematology, Respiratory Medicine and Oncology,Department of Internal Medicine, Faculty of Medicine, Saga University, Saga,Japan.Received: 5 May 2012 Accepted: 7 July 2013Published: 24 July 2013References1. Abbruzzese JL: Adjuvant therapy for surgically resected pancreaticadenocarcinoma. JAMA 2008, 299:1066–1067.2. Hilbig A, Oettle H: Adjuvant therapy of pancreatic cancer. Expert RevAnticancer Ther 2010, 10:485–491.3. Artinyan A, Anaya DA, McKenzie S, Ellenhorn JDI, Kim J: Neoadjuvanttherapy is associated with improved survival in resectable pancreaticadenocarcinoma. Cancer 2011, 117:2044–2049.4. O’Reilly EM: Adjuvant therapy for pancreas adenocarcinoma: where arewe going? Expert Rev Anticancer Ther 2011, 11:173–177.5. Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, Doi R,Monden M, Hatori T, Tanaka M, Shimada M, Kanemitsu K: A randomisedphase III trial comparing gemcitabine with surgery-only in patients withresected pancreatic cancer: Japanese Study Group of Adjuvant Therapyfor Pancreatic Cancer. Br J Cancer 2009, 101:908–915.6. Barlési F, Villani P, Doddoli C, Gimenez C, Kleisbauer J-P: Gemcitabine-induced severe pulmonary toxicity. Fundam Clin Pharmacol 2004,18:85–91.7. Boiselle PM, Morrin MM, Huberman MS: Gemcitabine pulmonary toxicity:CT features. J Comput Assist Tomogr 2000, 24:977–980.8. Gupta N, Ahmed I, Steinberg H, Patel D, Nissel-Horowitz S, Mehrotra B:Gemcitabine-induced pulmonary toxicity: case report and review of theliterature. Am J Clin Oncol 2002, 25:96–100.9. Kim YH, Mishima M, Yoshizawa A: Gemcitabine-induced acute eosinophilicpneumonia. J Thorac Oncol 2010, 5:1308–1309.10. Galvão FH, Pestana JO, Capelozzi VL: Fatal gemcitabine-inducedpulmonary toxicity in metastatic gallbladder adenocarcinoma. CancerChemother Pharmacol 2010, 65:607–10.Yakabe et al. World Journal of Surgical Oncology 2013, 11:167 Page 4 of 4http://www.wjso.com/content/11/1/16711. Johkoh T, Muller NL, Akira M, Ichikado K, Suga M, Ando M, Yoshinaga T,Kiyama T, Mihara N, Honda O, Tomiyama N, Nakamura H: Eosinophilic lungdiseases: diagnostic accuracy of thin-section CT in 111 patients.Radiology 2000, 216:773–780.12. Allen J: Acute eosinophilic pneumonia. Semin Respir Crit Care Med 2006,27:142–147.13. Hagio T, Matsumoto S, Nakao S, Abiru T, Ohno H, Kawabata K: Elastaseinhibition reduced death associated with acid aspiration-induced lunginjury in hamsters. Eur J Pharmacol 2004, 488:173–180.14. Higenbottam T, Kuwano K, Nemery B, Fujita Y: Understanding themechanisms of drug-associated interstitial lung disease. Br J Cancer 2004,91:S31–S37.doi:10.1186/1477-7819-11-167Cite this article as: Yakabe et al.: Severe eosinophilic pneumoniapresenting during gemcitabine adjuvant chemotherapy. World Journal ofSurgical Oncology 2013 11:167.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

Severe eosinophilic pneumonia presenting during gemcitabine adjuvant chemotherapy

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Severe eosinophilic pneumonia presenting during gemcitabine adjuvant chemotherapy

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