A 71-year-old Japanese man with adenocarcinoma of the lung developed interstitial pneumonia after treatment with paclitaxel. The patient had acute chills and fever on the fourth day after the second exposure to paclitaxel, rapidly got worse despite empiric therapies, and developed prolonged respiratory failure requiring mechanical ventilation. Four months later, he died of respiratory failure due to progression of both interstitial pneumonia and lung cancer. This is the first case developing fatal paclitaxel-induced pulmonary toxicity to date. Interstitial pneumonia should be considered one of the possible life-threatening complications during treatment with paclitaxel

Hiraki, Akio

Kanehiro, Arihiko

Kiura, Katsuyuki

Kozuki, Toshiyuki

Suzaki, Noriyuki

Tabata, Masahiro

Takigawa, Nagio

Tanimoto, Mitsune

Tanimoto, Yasushi

Ueoka, Hiroshi

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 60, Issue 5 2006 Article 6OCTOBER 2006Severe Interstitial Pneumonia Induced byPaclitaxel in a Patient with Adenocarcinoma ofthe LungNoriyuki Suzaki, Okayama UniversityAkio Hiraki, Okayama UniversityNagio Takigawa, Okayama UniversityHiroshi Ueoka, Okayama UniversityYasushi Tanimoto, Okayama UniversityToshiyuki Kozuki, Okayama UniversityMasahiro Tabata, Okayama UniversityArihiko Kanehiro, Okayama UniversityKatsuyuki Kiura, Okayama UniversityMitsune Tanimoto, Okayama UniversityCopyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Severe Interstitial Pneumonia Induced byPaclitaxel in a Patient with Adenocarcinoma ofthe Lung∗Noriyuki Suzaki, Akio Hiraki, Nagio Takigawa, Hiroshi Ueoka, YasushiTanimoto, Toshiyuki Kozuki, Masahiro Tabata, Arihiko Kanehiro, KatsuyukiKiura, and Mitsune TanimotoAbstractA 71-year-old Japanese man with adenocarcinoma of the lung developed interstitial pneu-monia after treatment with paclitaxel. The patient had acute chills and fever on the fourth dayafter the second exposure to paclitaxel, rapidly got worse despite empiric therapies, and developedprolonged respiratory failure requiring mechanical ventilation. Four months later, he died of res-piratory failure due to progression of both interstitial pneumonia and lung cancer. This is the firstcase developing fatal paclitaxel-induced pulmonary toxicity to date. Interstitial pneumonia shouldbe considered one of the possible life-threatening complications during treatment with paclitaxel.KEYWORDS: paclitaxel, adverse effect, lung cancer, interstitial pneumonia∗PMID: 17072376 [PubMed - in process]Copyright (C) OKAYAMA UNIVERSITY MEDICAL SCHOOLSevere Interstitial Pneumonia Induced by Paclitaxel in a Patient with Adenocarcinoma of the LungNoriyuki Suzakia,  Akio Hirakia,b,  Nagio Takigawaa＊,  Hiroshi Ueokaa,b,  Yasushi Tanimotoa,  Toshiyuki Kozukia,  Masahiro Tabataa,  Arihiko Kanehiroa,  Katsuyuki Kiuraa,  and Mitsune TanimotoaaDepartment of Respiratory Medicine,  Okayama University Hospital,  Okayama 700ﾝ8558,  Japan,  and bDepartment of Respiratory Medicine,  NHO Sanyo National Hospital,  Respiratory Disease Center,  Ube,  Yamaguchi 755ﾝ0241,  JapanA 71-year-old Japanese man with adenocarcinoma of the lung developed interstitial pneumonia after treatment with paclitaxel.  The patient had acute chills and fever on the fourth day after the second exposure to paclitaxel,  rapidly got worse despite empiric therapies,  and developed prolonged respira-tory failure requiring mechanical ventilation.  Four months later,  he died of respiratory failure due to progression of both interstitial pneumonia and lung cancer.  This is the ﬁ rst case developing fatal paclitaxel-induced pulmonary toxicity to date.  Interstitial pneumonia should be considered one of the possible life-threatening complications during treatment with paclitaxel.Key words : paclitaxel,  adverse eﬀ ect,  lung cancer,  interstitial pneumoniaaclitaxel (Taxol,  Bristol-Myers-Squibb, Princeton,  NJ,  USA) is a taxane anti-neoplas-tic agent with a broad spectrum of activity for vari-ous cancers.  Major adverse eﬀ ects are peripheral neuropathy,  myelotoxicity,  bradycardia,  hypoten-sion,  arthralgia,  myalgia,  granulocytopenia and hypersensitivity [1,  2].  Hypersensitivity reactions are well-recognized complications of paclitaxel administration and typically occur during the ﬁ rst or second exposure [3,  4].  These reactions,  consisting of dyspnea with or without bronchospasms,  urticaria, rashes,  hypotension,  or angioedema,  have been thought to be attributable to both paclitaxel itself and to its diluent,  Cremophor EL.  Because of the high incidence of hypersensitivity reactions,  a stan-dardized premedication regimen using high-dose dexamethasone,  diphenhydramine,  and cimetidine is prescribed for prophylaxis of paclitaxel-induced hypersensitivity reactions in Japan.　　Although several cases developing paclitaxel-induced interstitial pneumonia have been reported to date [5],  they have generally responded to cortico-steroid treatment.  A fatal case of paclitaxel-induced interstitial pneumonia has not been reported in the literature to date.  We describe here a patient with advanced adenocarcinoma of the lung developing acute life-threatening interstitial pneumonia on the fourth day after the second exposure to paclitaxel, and review the previous reports of interstitial pneu-monia induced by paclitaxel.PActa Med.  Okayama,  2006Vol.  60,  No.  5,  pp.  295ﾝ298http ://www.lib.okayama-u.ac.jp/www/acta/CopyrightⒸ 2006 by Okayama University Medical School.Case ReportReceived March 27, 2006 ; accepted May 22, 2006. ＊Corresponding author. Phone : ＋81ﾝ86ﾝ235ﾝ7227 ; Fax : ＋81ﾝ86ﾝ232ﾝ8226E-mail : ntakigaw@md.okayama-u.ac.jp (N. Takigawa)1Suzaki et al.: Severe Interstitial Pneumonia Induced by Paclitaxel in aProduced by The Berkeley Electronic Press, 2006Case Report　　A 71-year-old Japanese man was diagnosed with adenocarcinoma of the lung by the cytological exami-nation of pleural eﬀ usion at a local clinic and referred to our hospital.  He had a 40-pack-a-year history of cigarette smoking and no history of pulmo-nary disease.  He had been a clerical staﬀ  member at city hall,  and he had no allergic history.　　Physical examination on admission revealed a weakness of breath sounds in the right lung. Laboratory ﬁ ndings showed an elevated white blood cell (WBC) count (9,000/mm3),  serum levels of C-reactive protein (CRP : 7.3 mg/dl),  carcinoembry-onic antigen (CEA : 29.76 ng/ml),  progastrin releas-ing peptide (pro-GRP : 38.3 pg/ml),  sialyl Lewis-X-I antigen (SLX : 54.1 U/ml),  and neuron-speciﬁ c eno-lase (NSE : 18.70 ng/ml).  Arterial blood gas analysis revealed that the pH was 7.42,  PaO2 77.3 mmHg, and PaCO2 40.0 mmHg.  Computed tomography (CT) scans of the chest revealed a nodule on the right S3b, mediastinal lymph node swelling,  and right pleural eﬀ usion without interstitial lung disease.  Pulmonary function data were as follows : 1-second forced expi-ratory volume,  79.4ｵ ; vital capacity,  47.9ｵ ; car-bon monoxide diﬀ using capacity,  12.5 mL/min/mmHg (78.9ｵ).  After completion of the staging work-ups, the clinical stage was determined to be T4N2M1 (stage IV).  Systemic chemotherapy consisting of paclitaxel 80 mg/m2 (130 mg/body) by 1-hour intravenous infu-sion given on days 1 and 8 was started.  He was given premedication consisting of dexamethasone (16 mg), diphenhydramine (50 mg),  and ranitidine (50 mg).　　On day 12,  he felt feverish and had chills.  His temperature was 37.9 °C,  pulse 75/min,  blood pres-sure 138/80 mmHg,  respiratory rate 25/mim,  and oxygen saturation (SaO2) 90ｵ with room air. Arterial blood gas analysis showed that pH was 7.46, 296 Acta Med.  Okayama　Vol.  60,  No.  5Suzaki et al.A CB DFig. 1　　A,  Chest radiograph shows diﬀ use shadows in the left middle and lower lung ﬁ elds ; B,  CT scans of the chest demonstrate ground-glass opacities ; C,  D : Chest radiograph and CT scans of the chest showed extensive areas of ground-glass opacities and traction bronchiectasis.  The distribution was predominantly in the lower zone.2Acta Medica Okayama, Vol. 60 [2006], Iss. 5, Art. 6http://escholarship.lib.okayama-u.ac.jp/amo/vol60/iss5/6PaO2 63.5 mmHg,  and PaCO2 34.4 mmHg.  Mild ﬁ ne crackles were audible in the left lung.  The WBC count was 3,300/mm3,  including 70.0ｵ neutrophils and 22.0ｵ lymphocytes.  Serum levels of CRP,  lac-tate dehydrogenase,  and KL-6 were 15.0 mg/dl, 704 U/l,  and 1,139 U/ml,  respectively.  Culture of the sputum and peripheral blood detected no patho-genic organisms.  Serological tests for candida, mycoplasma,  pneumocystis jiroveci,  and cytomegalo-virus were negative.  The chest radiograph showed diﬀ use shadows in the left middle and lower lung ﬁ elds (Fig.  1A).  CT scans of the chest demonstrated ground-glass opacities (Fig.  1B).  We therefore determined that he had paclitaxel-induced interstitial pneumonia.　　He was immediately treated with steroid pulse therapy (methylprednisolone,  1 g/day for 3 days). Five days later,  since his symptoms and the intersti-tial shadows on the chest radiograph did not improve, he received the second cycle of steroid pulse therapy (methylprednisolone,  2 g/day for 3 days).  Further-more,  he was given cyclophosphamide (750 mg/day) on day 31 from the initiation of chemotherapy (10 days after the last pulse therapy),  but his general condition did not improve.  CT scans of the chest showed extensive areas of ground-glass opacities with interlobular septal thickening and traction bronchiec-tasis,  and the distribution was predominantly in the lower zone (Fig.  1 C,  D).  He was then intubated with mechanical ventilatory support the next day.  On day 128 from the initiation of chemotherapy,  he died of respiratory failure due to progression of intersti-tial pneumonia and lung cancer.  Autopsy was not allowed.Discussion　　Drug-induced interstitial pneumonia is a rare com-plication of paclitaxel administration.  There have been a few reports of paclitaxel-induced interstitial pneumonia to date.  Furuse et al. have reported that the incidence of interstitial pneumonia in patients with previously untreated advanced NSCLC is approximately 3ｵ in phase II [1],  but that it increases to approximately 50ｵ in patients with locally advanced NSCLC receiving concurrent radio-therapy [6].  Although premedication for paclitaxel administration is commonly carried out for prophy-laxis of hypersensitivity reactions,  the true eﬃ  cacy is still unconﬁ rmed because severe hypersensitivity reactions have been reported despite premedication, just as we experienced in this case.  Docetaxel and paclitaxel have similar mechanisms of action as microtubule-stabilizing drugs and have similar adverse eﬀ ects of interstitial pneumonia.  Although there have been several reports of severe interstitial pneumonia by docetaxel [7,  8],  this is the ﬁ rst known case to developing fatal paclitaxel-induced pul-monary toxicity.  Interstitial pneumonia induced by geﬁ tinib and leﬂ unomide tends to occur in Japanese more frequently than in Westerners [9,  10].  To our best knowledge,  interstitial pneumonia has not been reported in Western phase II studies of paclitaxel monotherapy,  although there have been a few case reports [4,  5,  11].  Two Japanese phase II studies, reported by Furuse et al. and Sekine et al.,  have shown the frequency of interstitial pneumonia to be 3ｵ and 1.7ｵ,  respectively [1,  2].  As such,  there may be ethnic diﬀ erences in the frequency of inter-stitial pneumonia by paclitaxel.　　The mechanism of drug-induced interstitial pneu-monia is not well understood.  Most researchers agree that it is the consequence of a cell-mediated immunologic reaction.  Drug-induced interstitial pneu-monia is diagnosed by a drug lymphocyte stimulation test (DLST) coupled with bronchoalveolar lavage or transbronchial lung biopsy ﬁ ndings.  However,  these examinations could not be performed in the present case due to severe respiratory failure caused by life-threatening pneumonia.  DLST using peripheral blood is also useful as an in vitro method of screening for drug allergy.  It should have been performed in this patient,  although the positive ratio was reported to be only 33ｵ [12] and a positive result does not indicate the drug responsible for the symptoms,  only a sensitization to that drug [13].  In the present case,  paclitaxel-induced pneumonia was diagnosed by excluding the other possible etiologies and consider-ing the clinical course.　　The ﬁ rst treatment for paclitaxel-induced intersti-tial pneumonia is the withdrawal of this drug.  Some patients developing paclitaxel-induced pneumonia improve spontaneously [11].  The second choice of treatment is administration of corticosteroid.  Usually prednisolone at a dose of 30 to 60 mg per day is given for 2 to 3 weeks,  and higher doses like pulse 297Severe Pneumonia Induced by PaclitaxelOctober 20063Suzaki et al.: Severe Interstitial Pneumonia Induced by Paclitaxel in aProduced by The Berkeley Electronic Press, 2006therapy are administered for more severe conditions such as acute respiratory failure,  with a slow and careful tapering-oﬀ  period.  Because paclitaxel-induced interstitial pneumonia usually responds rap-idly to steroid therapy [5,  11],  steroid-refractory cases have not been reported.  Although this patient had no history of pulmonary disease or thoracic radi-ation therapy,  he responded to neither an immuno-suppressive agent nor steroid pulse therapy.  In sev-eral cases,  predominant CT ﬁ ndings showed ground-glass opacities and interlobular septal thickening [14]. The CT images of drug-induced pneumonia are usu-ally classiﬁ ed into interstitial pneumonia/ﬁ brosis, diﬀ use alveolar damage,  organizing pneumonia reac-tion,  or a hypersensitivity reaction [15].  Ichikado et al. have reported that patients with acute interstitial pneumonia who have CT ﬁ ndings suggestive of the ﬁ broproliferative phase of diﬀ use alveolar damage, particularly ﬁ ndings of architectural distortion,  and ground-glass attenuation associated with traction bronchiectasis,  have a worse prognosis than patients without these ﬁ ndings [16].  In the present case,  CT ﬁ ndings showed ground-glass opacities and traction bronchiectasis,  which were compatible with acute lung injury characterized pathologically by diﬀ use alveolar damage [17].  If CT ﬁ ndings in paclitaxel-induced pneumonia show traction bronchiectasis dur-ing the acute phase,  the prognosis may be worse.　　In conclusion,  we have reported herein a case with advanced lung cancer developing paclitaxel-induced,  acute life-threatening interstitial pneumonia. Although this complication rarely occurs,  physicians should be alert to this unusual and possibly life-threatening adverse eﬀ ect of paclitaxel,  in order to begin treatment as soon as possible.References 1. Furuse K,  Naka N,  Takada M,  Kinuwaki E,  Kudo S,  Takada Y, Yamakido M,  Yamamoto H and Fukuoka M : Phase II study of 3-hour infusion of paclitaxel in patients with previously untreated stage III and IV non-small cell lung cancer.  West Japan Lung Cancer Group.  Oncology (1997) 54 : 298ﾝ303. 2. Sekine I,  Nishiwaki Y,  Watanabe K,  Yoneda S and Saijo N : Phase II study of 3-hour infusion of paclitaxel in previously untreated non-small cell lung cancer.  Clin Cancer Res (1996) 2 : 941ﾝ945. 3. Fujimori K,  Yokoyama A,  Kurita Y,  Uno K and Saijo N : Paclitaxel-induced cell-mediated hypersensitivity pneumonitis.  Diagnosis using leukocyte migration test,  bronchoalveolar lavage and trans-bronchial lung biopsy.  Oncology (1998) 55 : 340ﾝ344. 4. Wong P,  Leung AN,  Berry GJ,  Atkins KA,  Montoya JG,  Ruoss SJ and Stockdale FE : Paclitaxel-induced hypersensitivity pneumo-nitis : radiographic and CT ﬁ ndings.  Am J Roentgenol (2001) 176 : 718ﾝ720. 5. Sotiriou C,  van Houtte P and Klastersky J : Lung ﬁ brosis induced by paclitaxel.  Support Care Cancer (1998) 6 : 68ﾝ71. 6. Reckzeh B,  Merte H,  Pﬂ uger KH,  Pfab R,  Wolf M and Havemann K : Severe lymphocytopenia and interstitial pneumonia in patients treated with paclitaxel and simultaneous radiotherapy for non-small-cell lung cancer.  J Clin Oncol (1996)14 : 1071ﾝ1076. 7. Wang GS,  Yang KY and Perng RP : Life-threatening hypersensitiv-ity pneumonitis induced by docetaxel (taxotere).  Br J Cancer (2001) 85 : 1247ﾝ1250. 8. Read WL,  Mortimer JE and Picus J : Severe interstitial pneumoni-tis associated with docetaxel administration.  Cancer (2002) 94 : 847ﾝ853. 9. Cohen MH,  Williams GA,  Sridhara R,  Chen G,  McGuinn WD Jr, Morse D,  Abraham S,  Rahman A,  Liang C,  Lostritto R,  Baird A and Pazdur R : United States Food and Drug Administration Drug Approval summary : Gefitinib (ZD1839 ; Iressa) tablets.  Clin Cancer Res (2004) 10 : 1212ﾝ1218.10. McCurry J : Japan deaths spark concerns over arthritis drug. Lancet (2004) 363 : 461.11. Ramanathan RK,  Reddy VV,  Holbert JM and Belani CP : Pulmonary inﬁ ltrates following administration of paclitaxel. Chest (1996) 110 : 289ﾝ292.12. Kondo A : Drug-induced pnemomonitis.  Kekkaku (1999) 74 : 33ﾝ34 (in Japanese).13. Nakamura R,  Imamura T,  Onitsuka H,  Mishima K,  Ishikawa T, Nagoshi T,  Fujiura Y,  Date H,  Maeno M,  Matsuo T,  Koiwaya Y and Eto T : Interstitial pneumonia induced by ticlopidine.  Circ J (2002) 66 : 773ﾝ776.14. Akira M,  Ishikawa H and Yamamoto S : Drug-induced pneumoni-tis : thin-section CT ﬁ ndings in 60 patients.  Radiology (2002) 224 : 852ﾝ860.15. Cleverley JR,  Screaton NJ,  Hiorns MP,  Flint JD and Muller NL : Drug-induced lung disease : high-resolution CT and histologi-cal ﬁ ndings.  Clin Radiol (2002) 57 : 292ﾝ299.16. Ichikado K,  Suga M,  Muller NL,  Taniguchi H,  Kondoh Y,  Akira M, Johkoh T,  Mihara N,  Nakamura H,  Takahashi M and Ando M : Acute interstitial pneumonia : comparison of high-resolution computed tomography ﬁ ndings between survivors and nonsurvivors. Am J Respir Crit Care Med (2002) 165 : 1551ﾝ1556.17. Schwarz MA : Acute lung injury : cellular mechanisms and derangements.  Paediatr Respir Rev (2001) 2 : 3ﾝ9.298 Acta Med.  Okayama　Vol.  60,  No.  5Suzaki et al.4Acta Medica Okayama, Vol. 60 [2006], Iss. 5, Art. 6http://escholarship.lib.okayama-u.ac.jp/amo/vol60/iss5/6

Severe Interstitial Pneumonia Induced by Paclitaxel in a Patient with Adenocarcinoma of the Lung

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Severe Interstitial Pneumonia Induced by Paclitaxel in a Patient with Adenocarcinoma of the Lung

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