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Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2013, Article ID 683948, 5 pages http://dx.doi.org/10.1155/2013/683948 Case Report Granulomatous Lung Disease Requiring Mechanical Ventilation Induced by a Single Application of Oxaliplatin-Based Chemotherapy for Colorectal Cancer: A Case Report 1 1 1 1 1 Dane Wildner, Frank Boxberger, Axel Wein, Kerstin Wolff, Heinz Albrecht, 1 2 3 1 4 Gudrun Männlein, Rolf Janka, Kerstin Amann, Jürgen Siebler, Werner Hohenberger, 1 1 Markus F. Neurath, and Richard Strauß Department of Medicine 1, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany Radiological Institute, University Hospital Erlangen, Maximiliansplatz 1, 91054 Erlangen, Germany Institute of Pathology, University Hospital Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany Department of Surgery, University Hospital Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany Correspondence should be addressed to Dane Wildner; firstname.lastname@example.org Received 17 February 2013; Accepted 23 March 2013 Academic Editors: R. Martinez, S. Ohno, and R. Yamamoto Copyright © 2013 Dane Wildner et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Combined chemotherapeutic regimens in conjunction with oxaliplatin are considered safe and effective treatment options in the clinical management of metastatic colorectal cancer. A 62-year-old male patient with a metastatic rectal carcinoma developed a pulmonary reaction aeft r the first application of the combined standard chemotherapy regimen (5-fluorouracil and sodium folinic acid as a 24 h infusion and oxaliplatin). Following the first dose of chemotherapy, the patient developed acute dyspnoea and fever. A computerised scan of the chest revealed bilateral pulmonary patchy consolidation. Despite high-dose empiric antibiotic and antimycotic treatment, no clinical improvement was seen. eTh patient’s condition deteriorated, and he required invasive mechanical ventilation. Diagnostic thoracoscopic wedge resections were performed for further diagnosis. The histological workup revealed distinct granulomatous inflammation, but no microbial pathogens were to be found. er Th eupon, a drug-induced reaction to chemotherapy was suspected and high-dose steroid treatment initiated. Subsequently, the patient’s respiratory condition improved and he was extubated. The present case exemplifies the rare course of a bilateral pneumonia-like, drug-induced granulomatous reaction following a single application of oxaliplatin. In addition to the known side effects of oxaliplatin-containing combination chemotherapy, unexpected serious adverse events in the form of pulmonary toxicities should also be taken into account. 1. Introduction of life. In some cases, a secondary metastatic resection of primarily unresectable metastases aeft r downstaging oeff rs eTh standard palliative treatment of patients with metastatic acurativeoption. Anecessary proviso, however, is close colorectal cancer involving the application of 5-fluorouracil- interdisciplinary cooperation on the part of all those involved (5-FU-) based chemotherapy combined with irinotecan or [6, 7]. oxaliplatin in rfi st- and second-line treatment extended The occurrence of adverse events during chemotherapy patient survival by up to 22 months [1–3]. In addition, makes it necessary to modify or, in rare cases, even to innovative molecular approaches such as antiangiogenesis discontinue treatment. Depending on the treatment regimen or inhibition of signal epidermal growth factor receptor applied, the most frequent serious side effects that may occur transmission have become more important [4, 5]. Currently, following the use of oxaliplatin (in combination with) 5- the interdisciplinary management of colon cancer patients FU and folinic acid are haematological (13%–52%), gastroin- who initially do not respond to curative therapy is at the testinal (10%–33%), and neurological (0%–8%) toxicities. focus of efforts to prolong survival and maintain quality Although most of these reactions can be readily controlled, in 2 Case Reports in Oncological Medicine (a) (b) Figure 1: X-ray (one day aer ft inpatient admittance) and CT scan of the chest (one month prior to first chemotherapy administration). Normal finding in both lungs. rare cases they may necessitate discontinuation of treatment. patient’s third day in hospital, his antibiotic therapy was In comparison with the high level of oxaliplatin usage, adjusted to piperacillin/sulbactam and ciprofloxacin. From pulmonarytoxicityisveryrare[8–10]. the fth fi day onwards, u fl conazole was added. During the course of treatment, both the conventional X-ray and the CT 2. Case Presentation scan of the chest revealed bilateral patchy consolidations of both lungs and low-grade pleural effusions ( Figure 2). After A 62-year-old male patient attended the outpatient depart- seven days, the patient was transferred to the intensive care ment for endoscopic clarification of lower gastrointestinal unit with respiratory failure (O -saturation 70%). Antibi- bleeding haemorrhage. Since the patient had atrial b fi rilla- otic treatment was continued, and noninvasive mechanical tion, he was on phenprocoumon. Colonoscopy revealed a ventilation initiated. On the following day, however, the circular exulcerating carcinoma located in the upper third patient had to be intubated because of progressive respiratory of the rectum. Histological workup revealed an adenocarci- distress (arterial blood gases: FiO 0.55, paO 36.2 mmHg, 2 2 noma. Ultrasonography of the abdomen showed a number of pCO 46.7 mmHg, Horowitz-Index 65.8). Bronchoalveolar virtually hypoechoic lesions compatible with liver metastases. lavage was performed. Neither microbiological nor viro- Consequently, deep anterior rectal resection plus peritonec- logical examinations revealed the presence of pathogens. tomy in the region of the posterior wall of the bladder Ten days aeft r intubation, the patient’s gas exchange param- combined with a descendorectostomy were performed to eters showed no signs of clinical improvement (arterial resolve a high-grade stenosis caused by the rectal carcinoma. blood gases: FiO 1.0, paO 99 mmHg, pCO 43.0 mmHg, 2 2 2 Intraoperatively, peritoneal carcinomatosis was also found. Horowitz-Index 99). The laboratory markers of inflamma- The findings were categorized pathohistologically as pT4b, tion continued to increase (maximum values: leucocytes pN2 (5/28), L0, V1, pM1 (PER, HEP), and G2 (UICC 15.500/𝜇 L (normal range: 4.000–10.000/𝜇 L), CRP 174 mg/L StageIV).Thepostoperative course wasuneventful. Diffuse, (normal range< 5 mg/L)). Antibiotic medication was tem- nonresectable liver metastases and peritoneal carcinomatosis porarily discontinued, and thoracoscopic wedge resections were diagnosed, and palliative treatment with combina- were performed in all three right pulmonary lobes. Prior tion chemotherapy comprising high-dose 5-FU and sodium to the availability of the microbiological and histological folinic acid in the form of a 24 h infusion plus oxaliplatin results, antibiotic treatment with ceftazidime and fosfomycin every second week was scheduled . was applied. Neither the Grocott nor the Ziehl-Neelsen or One day aer ft receiving the first dose (5-FU 2.000 mg/m , Auramine staining revealed evidence of bacterial or mycotic sodium folinic acid 500 mg/m combined with a previ- pathology. Both the mycobacterial PCR and the bacterio- ous application of oxaliplatin 85 mg/m )the patientpre- logical cultures were negative. Repeated microbiological and viral examinations (bronchoalveolar lavage, bloodcultures, sented at our emergency unit with progressive dyspnoea andasubfebrile temperature(38.4 C). Laboratory mark- galactomannan assay, central venous catheter tip, urine, ers of inflammation were elevated (leucocytes 12.400/ 𝜇 L and legionella-antigens in the urine) all remained nega- (normal range: 4.000–10.000/𝜇 L), CRP 41 mg/L (normal tive. No signs of systemic autoimmune disease were to be range< 5 mg/L)). Empirical antibiotic treatment with ampi- found. The histological findings revealed extensive gran- ulomatous inflammation with no evidence of malignancy cillin/sulbactam was initiated. At that time the conventional chest X-ray and the previous computerised tomography of (Figure 3). No eosinophilic infiltration, fibroinflammatory the chest (obtained one month prior to the initiation of buds, or collagen bundles as evidence of a hypersensitivity reaction or pulmonary bro fi sis were seen. Since a drug- chemotherapy) were inconspicuous (Figure 1). Nevertheless, the patient’s condition continued to deteriorate. On the induced lung reaction to chemotherapy was suspected, i.v. Case Reports in Oncological Medicine 3 (a) (b) Figure 2: X-ray (seven days aeft r inpatient admittance) and CT scan of the chest (vfi e days aeft r initiation of chemotherapeutic treatment). Patchy airspace consolidation with peribronchial and peripheral distribution. Small pleural effusion bilaterally (black asterisk). Figure 4: CT scan of the chest vfi e months aeft r the first application Figure 3: Lung biopsy specimen obtained by video-assisted tho- of chemotherapy. Small scar in the right upper lobe (white arrow) racoscopic wedge resection (HE ×10). Extensive granulomatous and small pleural calcification (white arrowhead) as residual lesions inflammation. No evidence of b fi rosis or malignancy. of the inflammatory process. high-dose steroid treatment (initial application: 1 g pred- (5-FU and sodium folinic acid in the form of a 24 h infusion nisolone per day) was started. Within 36 hours, the gas plus weekly irinotecan) . All in all, the patient received exchange parameters improved, and the patient was extu- three cycles of palliative second-line treatment, one cycle batedaeft r4daysonsteroidtreatmentand16day s on invasive of palliative third-line treatment (5-FU and sodium folinic mechanical ventilation. During the following days, inter- acid in the form of a 24 h infusion combined with weekly mittent noninvasive mechanical ventilation was gradually irinotecan and cetuximab), one cycle of palliative fourth-line reduced and finally discontinued on the third postextubation treatment (5-FU and sodium folinic acid in the form of a day. eTh daily prednisolone dose was reduced to 70 mg aeft r 24 h infusion combined with irinotecan, and bevacizumab eight days, to 50 mg aer ft 12 days, and finally tapered off over every two weeks), and finally additional internal radiotherapy 3 weeks. (SIRT). The additional palliative treatment regimens were On discharging the patient from the inpatient depart- well tolerated, and no more serious toxic side effects occurred. ment, we reevaluated his clinical condition and radiological Pulmonary symptoms did not reoccur. From initiation of pal- findings and discussed his treatment options with him in liative rfi st-line treatment, the patient survived 21 months. He detail. His general state of health (ECOG 1) and alimentary died of tumour-associated cardiocirculatory failure caused by status were both good. A dihydropyrimidine-dehydrogenase progression of the liver metastases. deficiency, which is sometimes associated with high-grade 5- FU toxicity, was excluded. A CT scan of the chest 5 months aer ft respiratory failure ( Figure 4)showedvirtually complete 3. Discussion resolution with only slight residual subpleural scarring and pleural calcifications. Acute lung injury after combination chemotherapy including Finally, with the informed consent of the patient, oxaliplatin does occasionally occur. In view of the frequency we decided to implement palliative second-line treatment of such treatment, however, reports of acute respiratory 4 Case Reports in Oncological Medicine deterioration (sometimes taking a fatal course) associated a single administration of oxaliplatin has not so far been with the use of oxaliplatin are rare, and only a few publications reported. describe pulmonary fibrosis, hypersensitivity reactions, or organizing pneumonia [12–25]. Drug-induced pneumonitis 4. Conclusions is usually a diagnosis of exclusion. Symptoms are nonspecific and may include dyspnoea, fever, or respiratory failure. Clinical application of combined chemotherapy with oxali- Infections,alveolarhaemorrhage,lymphangiosis,and heart platin is considered a safe and efficient method of treating failure are the main differential diagnoses in cancer patients advanced colorectal cancer. Apart from the consideration on chemotherapy who develop respiratory distress. In our of haematological, gastrointestinal, and neurological side patient, extensive diagnostic workup, which included blood, effects, possible pulmonary toxicities should also be taken bronchoalveolar lavage, urine, and histological examinations, into account. Lung biopsy should be considered in otherwise failed to produce a specific diagnosis. Retrospectively, no unexplained pulmonary disease in patients with chemother- pathogens were ever detected, despite extensive diagnostic apy. measures during the period of hospitalisation, and the response to empirical broad-spectrum antibiotic treatment Abbreviations failed to bringabout anyconsistentclinicalimprovement. A lung biopsy viathoracoscopic wedge resection in all three 5-FU: 5-Fluorouracil right pulmonary lobes was deemed necessary. The histo- UICC: Union Internationale Contre le Cancer logicalworkupofall threelobes showed thesamepattern CRP: C-reactive protein of a granulomatous infiltration with no signs of pulmonary PCR: Polymerase chain reaction fibrosis or malignancy. This patient report is the rfi st to ECOG: Eastern cooperative oncology group describe acute lung injury with a distinct granulomatous CT: Computed tomography reaction associated with this combination of drugs. No SIRT: Selective internal radiotherapy othercausesofgranulomatous lung disease(e.g. sarcoidosis, BCG: Bacillus Calmette-Guer ´ in Wegener disease, or mycobacterial infection) were to be TNF-𝛼 : Tumour necrosis factor-alpha. found. The rapid and sustained improvement achieved with high-dose steroid therapy in the absence of any signs of Authors’ Contribution autoimmune disease permits the conclusion to be drawn that the inflammatory changes had been caused by a drug- D. Wildner and F. Boxberger contributed equally to this work. induced pulmonary reaction. Since the concomitant medication was unlikely to be Acknowledgment responsible for the initial findings, the pathological course must have been caused by the oxaliplatin. Aeft r having Cedric Morris is acknowledged for language assistance. survived the acute reaction, the patient underwent repeated treatment with palliative combination therapy with 5-FU and References sodium folinicacidinaddition to otheragentsinthe second-, third-, and fourth line treatments.  C. Tournigand, T. Andre, ´ E. Achille et al., “FOLFIRI followed Reexposure to 5-FU and sodium folinic acid did not pro- by FOLFOX6 or the reverse sequence in advanced colorectal voke any signs of pulmonary toxicity. 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