oxaliplatin-induced interstitial lung disease

LETTER TO THE EDITOR – CLINICAL CASE NOTES

Oxaliplatin-induced interstitial lung disease

Francesco PICCOLO,1 Kynan T FEENEY,2 Anthony E TRIBE,1,4 Phil J THOMPSON,1,3,4

Michael J MILLWARD2,3 and Guy A van HAZEL2

Departments of 1Respiratory Medicine and 2Medical Oncology, Sir Charles Gairdner Hospital, 3School of Medicine andPharmacology, University of Western Australia and 4Lung Institute of Western Australia, Nedlands, Western Australia,Australia

Abstract

Oxaliplatin-induced lung disease is an increasingly recognised phenomenon. We describe here three cases ofpresumed oxaliplatin-induced interstitial lung disease. With increasing use of oxaliplatin for colorectalcancer, awareness of this complication and the need for early diagnosis and treatment of respiratorysymptoms can lead to early cessation of chemotherapy, rapid exclusion of alternative diagnoses andinitiation of treatment with corticosteroids.

Key words: drug reaction, interstitial lung disease, oxaliplatin, pneumonitis.

INTRODUCTION

Oxaliplatin in combination with 5-fluorouracil and leu-covorin (FOLFOX) is currently standard adjuvanttreatment for stage III colon carcinoma.1 FOLFOX che-motherapy has been shown to increase disease-free sur-vival in patients with stage III colon cancer. Oxaliplatin-based chemotherapy is also very effective in metastaticcolorectal carcinoma; thus, most patients with stage IIIor IV colorectal carcinoma will receive oxaliplatin-containing chemotherapy at some point during theirmanagement.2–4

Oxaliplatin is usually a well-tolerated chemothera-peutic agent. The toxicity profile of oxaliplatin is dif-ferent to cisplatin, with the most frequent adverseeffects including parasthesia and neuropathy (includingpharyngolaryngeal dysthesia and cold-induced sensoryneuropathy) (92%), neutropenia (79%), thrombocy-topenia (77%), anaemia (76%), diarrhea (56%) andvomiting (47%).1,5 Most of these adverse reactions arelow-grade.

We describe here three cases, seen over a two-yearperiod, of interstitial pneumonitis consistent with early-onset chemotherapy induced lung injury secondary tooxaliplatin.1 These cases had similar clinical presenta-tions with all three developing initial, non-specific symp-toms either towards the end or at the completion of theiradjuvant FOLFOX chemotherapy. They all requiredhospital admission, oxygen supplementation and in onecase intensive care admission for invasive ventilation.

CASES

Case 1

A 70-year-old man with a history of stage III coloncarcinoma underwent anterior resection followed byadjuvant chemotherapy with FOLFOX (oxaliplatin100 mg/m2, leucovorin 20 mg/m2 and fluorouracil400 mg/m2 on day 1, followed by a 46-h infusion offluorouracil 2400 mg/m2 every 14 days). After his 10thcycle of chemotherapy, he developed a non-specificdry cough. He partially completed his 11th cycle ofFOLFOX because of port problems and it was decidednot to proceed with the last cycle of chemotherapy. Oneweek after his last dose of FOLFOX the patient devel-oped increasing exertional dyspnoea and a dry cough.These symptoms progressively deteriorated over thenext three weeks to shortness of breath on exertion.Twenty-eight days after his last dose of oxaliplatin, he

Correspondence: Dr Kynan T Feeney, Department ofMedical Oncology, Sir Charles Gairdner Hospital, VerdunStreet, Nedlands WA 6009, Australia.Email: [email protected]

Accepted for publication 1 June 2008.

Asia–Pacific Journal of Clinical Oncology 2008; 4: 175–180 doi:10.1111/j.1743-7563.2008.00187.x

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

mailto:[email protected]

presented to the emergency department, dyspnoeic andcyanotic. His cough persisted, but there was no sputumproduction, fever, rigors or constitutional symptoms.

The patient had a past history of mild emphysemathat was asymptomatic and first diagnosed on a pre-operative CT scan, as well as atrial fibrillation, type 2diabetes mellitus and osteoarthritis. He was anex-smoker with a 50-pack per year smoking history. Hismedications were low-dose amiodarone, warfarin, met-formin and gliclazide.

On examination he was tachypnoeic (36 breaths/min), afebrile and his oxygen saturation at room air was

82%. Chest examination revealed fine inspiratory crack-les and occasional expiratory wheeze. Routine investi-gations, including ECG, hematology and biochemistry,and autoimmune screen were normal. Sputum culturesand serology for respiratory pathogens were negative.

The chest radiograph (CXR) showed bilateral inter-stitial infiltrates. A high-resolution (HR) computedtomography (CT) scan showed bilateral widespreadhoneycomb pattern with associated ground glass opaci-fication consistent with pulmonary fibrosis and alveolitis(Fig. 1). A baseline CT scan of his abdomen prior tostarting chemotherapy, which included the lower chestwas normal.

Respiratory function tests showed reduced lungvolume, with increased maximal expiratory flow ratesrelative to lung volume, and a severe reduction in trans-fer factor, consistent with interstitial lung disease(Table 1). His blood tests were normal, including anormal eosinophil count.

Five days after admission the patient was commencedon high-dose corticosteroids, but showed only modestimprovement in his symptoms, spirometry and radiol-ogy after eight weeks. His steroid dose was tapered andhe was started on daily cyclophosphamide. He remainedsymptomatic, with exertional dyspnoea nine monthsafter the onset of his symptoms, and required domicili-ary low-flow oxygen at home. He did not have any CTscans or lung function tests at follow-up.

Case 2

A 62-year-old man with stage III colon cancer received12 cycles of adjuvant FOLFOX chemotherapy (oxalipl-atin 100 mg/m2, leucovorin 20 mg/m2 and fluorouracil400 mg/m2 on day 1, followed by a 46-h infusion offluorouracil 2400 mg/m2 every 14 days). One week

Figure 1 Computed tomography scan of case 1 on presenta-tion to the emergency department.

Table 1 Lung function tests on initial presentation with dyspnoea and after steroid treatment in cases 1 and 2

Case 1 Case 2

On presentation toemergency department

(% predicted)

Followingsteroid treatment

(% predicted)

On presentation toemergency department

(% predicted)

Followingsteroid treatment

(% predicted)

TLC (L) 64 67 64 69RV (L) 67 58 67 53FVC (L) 53 83 53 72FEV1 (L) 47 84 47 73FEV1/FVC (%) 89 101 89 102DLCO (mL/min/mmHg) 22 20 22 40DLCO/EAV (mL/min/mmHg/L) 35 33 35 63

DLCO, diffusion capacity for Carbon Monoxide; DLCO/EAV, diffusion capacity for carbon monoxide/effective alveolar volume; FEV1, forcedexpiratory volume in the first second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.

176 F Piccolo et al.


Asia–Pac J Clin Oncol 2008; 4: 175–180

following his last dose of FOLFOX he developed pro-gressive exertional dyspnoea over a three-week period.There was no associated cough, fever, chills, rashes orchest pain. He had no history or respiratory disease andquit smoking five years ago after a 15-pack per yearsmoking history. His medications were clopidogrel, ator-vastatin, paracetamol and codeine phosphate.

On examination he was afebrile, with a pulse oxim-etry reading of 94% at room air, which decreased to89% with ambulation on the ward. Cardiorespiratoryexamination was normal. Blood tests were unremark-able, except for a mild eosinophilia of 0.56 ¥ 109/m2

(normal range = 0.0–0.4 ¥ 109/m2)–.His pre-chemotherapy staging CT scan demonstrated

mild emphysema and a CT scan performed only twomonths prior to his presentation mid-way throughhis chemotherapy demonstrated no new changes(see Fig. 2a). After admission, a high-resolution CT scanof the chest showed widespread bilateral pulmonaryinfiltrates consisting of subpleural ground glass opacifi-cation and an organising pneumonia (Fig. 2b). Pulmo-nary function tests showed reduced lung volumes withdecreased gas transfer consistent with interstitial lungdisease (Table 1).

The patient was treated with high-dose oral predniso-lone. He improved symptomatically and was able toambulate without difficulty. He was weaned off high-dose steroids after approximately two months. Repeatlung function testing six weeks after initiation of high-dose steroid treatment showed improvement in lungvolume, but persisting moderate reduction in gas trans-fer (Table 1). Repeat imaging of his chest 15 weeks afterhis initial presentation demonstrated significant resolu-tion of his previous inflammatory changes (Fig. 2c). Atfollow-up six months after his initial presentation hecontinued to be stable with no recurrence of his canceror respiratory symptoms.

Case 3

A 43-year-old woman with stage III colon cancer wasinitially treated with adjuvant capecitabine and oxalipl-atin chemotherapy. She had no history of respiratorydisease and was a non-smoker. She was not taking anypre-treatment medications. After four cycles she ceasedthis regimen due to poor tolerance (diarrhea, abdominalcramps and stomatitis) and commenced FOLFOX che-motherapy (oxaliplatin 100 mg/m2, leucovorin 20 mg/m2

and fluorouracil 400 mg/m2 on day 1, followed by a 46-hinfusion of fluorouracil 2400 mg/m2 every 14 days). Apre-treatment CT scan demonstrated normal lungs.

Within five minutes of completing her fifth cycle ofFOLFOX chemotherapy, the patient developed mildshortness of breath and a dry non-productive cough thatwas not considered severe enough for further investiga-tion. The shortness of breath resolved over the next fewhours, but a mild, dry cough persisted for the followingtwo weeks. Two weeks later, shortly after completingher last cycle of oxaliplatin, she developed acute short-ness of breath, fever and rigors. The patient was thentransferred to the emergency department where she wasfound to be febrile (38.9C), tachypnoeic (respiratoryrate 30 breaths/min) and hypoxemic (peripheral satura-tion at room air = 78%). She was admitted to hospitaland was started on broad-spectrum antibiotics for pre-sumed atypical pneumonia. She deteriorated rapidlyover the next 24 h, requiring admission to the intensivecare unit (ICU) for non-invasive positive pressure venti-lation. On day 3 of her admission, she continued todecline despite broader spectrum antibiotics, antifungalsand antivirals, and required endotracheal intubation. Anurgent bronchoscopy was performed, which demon-strated an intense granulocytic infiltrate with predomi-nance of eosinophils (63%) on bronchoalveolar lavage(BAL). This correlated with a peripheral blood eosino-philia (4.1 ¥ 109/m2, normal range = 0.0–0.4 ¥ 109/m2).

Her admission CXR demonstrated only a mild basalinfiltrate that rapidly deteriorated over the next threedays to a widespread, bilateral infiltrate by the time shewas intubated. A CT scan of her chest on the day of hertransfer to ICU revealed patchy infiltrates, dense pleural-based opacities in the apical segments of both lungs andsmall bilateral effusions (Fig. 3a,b). Serology, blood cul-tures, and BAL did not detect an infective cause for hersymptoms.

Intravenous steroids (hydrocortisone) were com-menced on day 4 of her admission, with swift resolutionof her symptoms and extubation. She was extubated onday 7 and discharged from ICU on day 8 of her admis-sion. Her CXR also demonstrated significant improve-ment within 24 h of starting corticosteroids. Her anti-infective agents were ceased and she was started on oralprednisolone on discharge from ICU. Her peripheraleosinophilia resolved and her inflammatory markerssuch as C-reactive protein dramatically improved, whichpeaked 247 mg/L at the time of intubation and reducedto 9 mg/L one week later (<8 mg/L normal).

A flare-up of her symptoms occurred one week afterher admission due to her steroid dose being reduced tooearly with quick resolution of symptoms after reinstitu-tion of her prednisolone to 50 mg/d. She was continuedon prednisolone at 50 mg/d for two months, with com-

Oxaliptatin-induced pneumonitis 177



plete clinical and radiological resolution of her symp-toms (Fig. 3c). The patient remains well 17 months afterher admission and has returned to full-time work withno impairment in her respiratory function.

DISCUSSION

Lung toxicity from chemotherapy has been well-described from a wide range of chemotherapeuticagents.6 Early-onset chemotherapy-induced lung injuryoccurs within two months of exposure to chemotherapy,and can be further sub-classified by its primary clinicalmanifestations, namely an interstitial pneumonitis, pul-monary edema, bronchospasm and pleural effusion.6

Oxaliplatin-induced lung damage is an infrequenttoxicity and only a small number of case reportsexist.7–14 Over the time period of observation in thetreating institutions, approximately 120 patients weretreated for both metastatic and adjuvant colorectal car-cinoma with oxaliplatin-containing regimens. In themajority of the reported cases, the onset of symptomsoccurred either towards the end of therapy or soon aftercompletion of chemotherapy.7–14

The cases reported herein represent early-onsetoxaliplatin-induced inflammatory interstitial pneumoni-tis. In each case, there was a strong temporal relation-ship with the use of oxaliplatin and previous lungimaging failed to show any evidence of interstitial lungdisease. Other potential diagnoses, such as autoimmunedisease, infection and cardiac failure, were excluded ascauses for these patient’s symptoms. Fluorouracil andleucovorin are not known to cause interstitial lungdisease.6 High resolution CT showed bilateral wide-spread infiltrates and ground glass opacification consis-tent with pulmonary alveolitis. Pulmonary function testsdemonstrated reduced lung volumes with a restrictivepattern and reduced gas transfer.

Adverse drug reactions in the lung are diverse. Thepatients described herein suggest that oxaliplatin maycause a spectrum of pulmonary responses. Case 1 stabi-lised on steroid treatment, but was left with persistingshortness of breath, radiographic changes and reducedgas transfer. Although case one was taking amiodarone

a

b

c

Figure 2 (a) Baseline computed tomography (CT) scan ofcase 2 prior to the development of respiratory symptoms. (b)CT scan of case 2 after presentation with respiratory symp-toms. (c) Repeat CT scan of case 2, 15 weeks after initialpresentation and treatment with steroids.�




previously, and we cannot exclude this as a possiblecause of his symptoms, the clinical picture is consistentwith an allergic alveolitis and resulting fibrosis second-ary to oxaliplatin that was not reversible with steroids.Case 2 had two months of steroid treatment withsymptomatic improvement, resolution of radiographicchanges and improvement in respiratory function tests;consistent with extrinsic alveolitis with a partialresponse to steroids. Case three is consistent with asevere allergic reaction leading to a drug-induced pul-monary eosinophilic pneumonia with complete recoveryfollowing an eight-week course of corticosteroids.

Oxaliplatin is increasingly being used as a standardpart of combined chemotherapy for treating stage IIIcolon cancer in the adjuvant, curative-intent setting.Although oxaliplatin-induced acute lung damage is rare,it is important for clinicians to be aware of this life-threatening toxicity and the diversity of reactions thatcan occur. In both cases 2 and 3, there were subtlerespiratory symptoms (mild shortness of breath, cough)prior to the more florid clinical presentation that led toadmission to hospital. This probably represented mild,self-limiting episodes of pneumonitis that with contin-ued exposure to oxaliplatin progressed to more severeinflammation.

Early investigation of respiratory symptoms can leadto early cessation of chemotherapy, rapid exclusion ofalternative diagnoses and initiation of treatment withcorticosteroids. We postulate that early initiation of cor-ticosteroids and cessation of chemotherapy is importantin the prevention of more severe, permanent damage. Incase 3, initiation of steroids led to improvement in symp-toms and total resolution of radiological evidence ofprevious lung inflammation, and in the other two cases, itled to improvement or stabilisation of symptoms.

Although our patients had little in the way of pre-existing lung disease it has been suggested that pre-existing lung pathology might increase susceptibility toadverse pulmonary responses to oxaliplatin and possiblythis group of patients should be monitored more closelyduring therapy.14

With the increasing use of oxaliplatin in the adjuvantsetting, careful monitoring of patients during andtowards the end of treatment seems sensible. Further

a

b

c

Figure 3 (a) Computed tomography (CT) scan of case 3 onthe day of transfer to the intensive care unit (ICU). (b) CT scanof case 3 on the day of transfer to ICU. (c) Repeat CT scan ofcase 3 after treatment with corticosteroids and resolution ofsymptoms.�

Oxaliptatin-induced pneumonitis 179



research is needed to clarify the mechanisms and classi-fication of toxicity, the role of pulmonary monitoringand whether pre-existing lung disease is a risk factor foradverse responses to oxaliplatin.

REFERENCES

1 Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin,fluorouracil, and leucovorin as adjuvant treatment forcolon cancer. N Engl J Med 350: 2343–51.

2 Andre T, Bensmaine MA, Louvet C et al. Multicenterphase II study of bimonthly high-dose leucovorin, fluorou-racil infusion, and oxaliplatin for metastatic colorectalcancer resistant to the same leucovorin and fluorouracilregimen. J Clin Oncol 1999; 17: 3560–8.

3 Giacchetti S, Perpoint B, Zidani R et al. Phase III multi-center randomized trial of oxaliplatin added to chrono-modulated fluorouracil-leucovorin as first-line treatment ofmetastatic colorectal cancer. J Clin Oncol 2000; 18: 136–47.

4 de Gramont A, Figer A, Seymour M et al. Leucovorin andfluorouracil with or without oxaliplatin as first-line treat-ment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938–47.

5 Rabik CA, Dolan ME. Molecular mechanisms of resistanceand toxicity associated with platinating agents. CancerTreat Rev 2007; 33: 9–23.

6 Meadors M, Floyd J, Perry MC. Pulmonary toxicity ofchemotherapy. Semin Oncol 2006; 33: 98–105.

7 Trisolini R, Lazzari Agli L, Tassinari D et al. Acute lunginjury associated with 5-fluorouracil and oxaliplatin com-bined chemotherapy. Eur Respir J 2001; 18: 243–5.

8 Gagnadoux F, Roiron C, Carrie E, Monnier-Cholley L,Lebeau B. Eosinophilic lung disease under chemotherapywith oxaliplatin for colorectal cancer. Am J Clin Oncol2002; 25: 388–90.

9 Jung KH, Kil SY, Choi IK et al. Interstitial lung diseases inpatients treated with oxaliplatin, 5-fluorouracil and leuco-vorin (FOLFOX). Int J Tuberc Lung Dis 2006; 10: 1181–2.

10 Ruiz-Casado A, Garcia MD, Racionero MA. Pulmonarytoxicity of 5-fluorouracil and oxaliplatin. Clin TranslOncol 2006; 8: 624.

11 Yague XH, Soy E, Merino BQ, Puig J, Fabregat MB,Colomer R. Interstitial pneumonitis after oxaliplatin treat-ment in colorectal cancer. Clin Transl Oncol 2005; 7:515–17.

12 Pasetto LM, Monfardini S. Is acute dyspnea related tooxaliplatin administration? World J Gastroenterol 2006;12: 5907–8.

13 Garrido M, O’Brien A, Gonzalez S, Clavero JM, OrellanaE. Cryptogenic organizing pneumonitis during oxaliplatinchemotherapy for colorectal cancer: case report. Chest2007; 132: 1997–9.

14 Wilcox BE, Ryu JH, Kalra S. Exacerbation of pre-existinginterstitial lung disease after oxaliplatin therapy: a reportof three cases. Respir Med 2008; 102: 273–9.




oxaliplatin-induced interstitial lung disease

Documents