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Year : 2010  |  Volume : 6  |  Issue : 4  |  Page : 546-548

Interstitial lung disease associated with FOLFOX chemotherapy

1 Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
2 Department of Emergency Medicine, Ilsan Paik Hospital, Inje University, Gyeonggi-do, Korea
3 Department of Internal Medicine, Konkuk University Medical Center, Chungju, Korea

Date of Web Publication24-Feb-2011

Correspondence Address:
Moon Hee Lee
Department of Internal Medicine, Inha University Hospital and College of Medicine, 7-206, 3rd Street, Shinheuong-dong, Jung-gu, Incheon 400-711
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Source of Support: INHA UNIVERSITY Research Grant, Conflict of Interest: None

DOI: 10.4103/0973-1482.77066

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 > Abstract 

Currently, FOLFOX regimen has been widely used as an effective approach for treating many advanced GI tract cancers. Toxicity induced by oxaliplatin has been well known and mostly moderate and manageable. Gastrointestinal, hematological and neurosensory toxicities are the most common. However, information concerning the pulmonary toxicity of this regimen is very limited and only a few cases of severe lung toxicity associated with FOLFOX chemotherapy have been reported. Here, we report a fatal case of interstitial lung disease which was associated with FOLFOX chemotherapy in metastatic advanced gastric cancer. The patient expired from progressive respiratory failure. This case suggests that FOLFOX-induced interstitial lung disease should be considered in the differential diagnosis of new lung lesions in patients who are treated with FOLFOX chemotherapy. And further investigations of possible association that may lead to acute respiratory failure are warranted.

Keywords: FOLFOX, gastric cancer, interstitial lung disease

How to cite this article:
Lim JH, Kim H, Choi WG, Lee MH. Interstitial lung disease associated with FOLFOX chemotherapy. J Can Res Ther 2010;6:546-8

How to cite this URL:
Lim JH, Kim H, Choi WG, Lee MH. Interstitial lung disease associated with FOLFOX chemotherapy. J Can Res Ther [serial online] 2010 [cited 2022 Jul 1];6:546-8. Available from: https://www.cancerjournal.net/text.asp?2010/6/4/546/77066

 > Introduction Top

Pulmonary toxicity associated with chemotherapeutic agents is not uncommon. These clinical syndromes include pneumonitis, fibrosis, noncardiogenic pulmonary edema or hypersensitivity lung disease. Lung toxicity associated with bleomycin or nitrosoureas has been extensively studied. There are additional reports of lung injury after cytarabine, gemcitabine, docetaxel, vinblastine, methotrexate, doxorubicin use. [1] Some of the more recent anticancer drugs, such as oxaliplatin, still have not been evaluated in this setting.

Oxaliplatin is a third-generation platins like trans-L-1,2-diaminocyclohexane combined with DNA to form DNA repair-resistant adducts. [2] Treatment with oxaliplatin in combination with 5-FU and leucovorin is usually used for the treatment of metastatic colorectal cancer and advanced gastric cancer in Korea. [3],[4],[5] Pulmonary toxicity of FOLFOX regimen is unusual; only few such cases have been reported. [6],[7],[8] Herein, we report a case who suffered from a fatal progression of interstitial lung disease which may be associated with FOLFOX chemotherapy in advanced gastric cancer patients.

 > Case Report Top

A 64-year-old male patient with a history of metastatic gastric cancer admitted for progressive dyspnea on exertion. Dyspnea developed several days before. This patient was diagnosed as advanced gastric cancer for four months ago. An endoscopy showed a gastric tumor, biopsy confirmed pathologically signet ring cell feature adenocarcinoma. Chest X-ray at the time of diagnosis revealed no-specific findings. Computed tomography of abdomen exhibited multiple lymphadenopathy in celiac trunk, paraaotic and retrocaval space with fatty infiltration and multiple nodules in omentum and mesentery and ascites suggesting peritoneal seeding. A positron emission tomography scan also showed the presence of hypermetabolic lesion in significant lymphadenopathy in left supraclavicular, mediastinal, and abdomen [Figure 1]. Chemotherapy using the FOLFOX-4 regimen was administered to the patient. After receiving eight treatment cycles with a partial response by REICIST response criteria and good tolerability except for grade 2 thrombocytopenia and grade 1-2 peripheral neuropathy by CTCAE v3.0, the patient compliant to experience progressive dyspnea eventually occurred on exertion with dry cough. Chest X-rays [Figure 2] showed bilateral interstitial infiltrates. Arterial blood gas analysis showed mild hypoxemia. The patient was admitted to our hospital and oxygen supplement was done.
Figure 1: Positron emission tomographic finding showing multiple lymph nodes enlargement in left supraclavicular, mediastinal, and perigastric area

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Figure 2: Chest PA exhibiting bilateral interstitial alveolar infiltrates

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Broad spectrum antibiotics for suspect of pneumonia were started. Multiple subsequent blood, sputum, and urine cultures failed to demonstrate any infection source. Because of the absence of response to empirical antibiotic therapy, we planned bronchoscopic examination. However, bronchoscopy including bronchoalveolar lavage also did not identify any infections agent, with no pathological findings. Although empirical antibiotics such as vancomycin, cefepime and ciprofloxacin were administered, the patient continued to worsen. We could rule out an infectious etiology. Follow-up CT scan of chest was performed and revealed a reticular interstitial involvement with a peripheral distribution and predominating at the bases with ground-glass appearance with thickening of interlobular septa related to pulmonary fibrosis. Small amount of pleural effusion was also revealed in both lungs [Figure 3]. Because of the possibility of interstitial lung disease, treatment was started with high-dose corticosteroids (2 mg/kg). However, the clinical course was unfavorable. His oxygenation worsened further and he needed intubation with mechanical ventilatory support. He ultimately expired to refractory respiratory failure after 10 days of mechanical ventilation. An autopsy request was declined from his family.
Figure 3: Chest CT image showing interstitial lung involvement predominantly affecting peripheral lung

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 > Discussion Top

We report a clinical case of lung toxicity after FOLFOX chemotherapy. FOLFOX regimen has become part of the standard treatment in a high number of patients with many gastrointestinal cancers. In clinical and preclinical studies, it has been established the toxicity in relation to its use. The major toxicities are peripheral sensory neuropathy, hematological and gastointestinal toxicities. Early safety trials evaluating oxaliplatin treatment found no significant increase in pulmonary complications, except for the dyspnea which may occur in the setting of infusion and hypersensitivity reaction. [9],[10] Common causes of lung complication in cancer patients are infection, pulmonary hemorrhage, lymphangitic lung metastasis, congestive heart failure, pulmonary embolism, and drug-induced lung toxicity. [11] Our patient had a rapidly progressive respiratory insufficiency that was refractory to conventional empirical antibiotics treatment. No infections causes triggering the clinical feature could be identified. Most cases of pulmonary toxicity associated with FOLFOX regimen reported in the literature had a rapid and untoward course like our case. [1],[11],[12] There is no objective evidence relating oxaliplatin to direct damage to lung parenchyma. However, there were data suggesting that oxaliplatin may cause glutathione depletion, which could be involved in the pathogenesis of liver damage caused by the drug and would be related to endothelial and perivascular damage and obstruction of hepatic sinusoids. [13] In the lung, glutathione also plays a significant role as protector against oxidative damage, and several parenchymal lung diseases have been proposed to be due to the exposure of the lung to exogenous irritants leading to local redox imbalance in the alveolar epithelium. [12] This imbalance caused by oxaliplatin could be the factor of the interstitial pneumonitis. Clinicians should keep in mind that use of some chemotherapeutic drug such as FOLFOX regimen may result in certain infrequent complications which is not revealed in clinical trials that may be fatal, and caution should therefore be taken when indicating treatments.

In conclusion, we report a patient of interstitial lung disease who experienced worsening of their respiratory symptom which may be associated with FOLFOX chemotherapy and led to death from respiratory failure. This case suggests that FOLFOX-induced interstitial lung disease should be considered in the differential diagnosis of new lung lesions in patients who are treated with oxaliplatin chemotherapy. Further investigations of possible association that may lead to acute respiratory failure are warranted.

 > Acknowledgments Top

This work was supported by INHA UNIVERSITY Research Grant.

 > References Top

1.Yague XH, Soy E, Merino BQ, Puig J, Fabregat MB, Colomer R. Interstitial pneumonitis after oxaliplatin treatment in colorectal cancer. Clin Transl Oncol 2005;7:515-7.  Back to cited text no. 1
2.Raymond E, Faivre S, Woynarowski JM, Chaney SG. Oxaliplatin: Mechanism of action and antineoplastic activity. Semin Oncol 1998;25:4-12.  Back to cited text no. 2
3.Kim YS, Hong J, Sym SJ, Park SH, Park J, Cho EK, et al. Oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX-4) combination chemotherapy as a salvage treatment in advanced gastric cancer. Cancer Res Treat 2010;42:24-9.  Back to cited text no. 3
4.Zhao JG, Qiu F, Xiong JP, Zhang L, Xiang XJ, Yu F, et al. A phase II study of modified FOLFOX as first-line chemotherapy in elderly patients with advanced gastric cancer. Anticancer Drugs 2009;20:281-6.  Back to cited text no. 4
5.Overman MJ, Varadhachary GR, Kopetz S, Adinin R, Lin E, Morris JS, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009;27:2598-603.  Back to cited text no. 5
6.Muneoka K, Shirai Y, Sasaki M, Wakai T, Sakata J, Hatakeyama K. Interstitial pneumonia arising in a patient treated with oxaliplatin, 5-fluorouracil, and, leucovorin (FOLFOX). Int J Clin Oncol 2009;14:457-9.  Back to cited text no. 6
7.Correale P, Fulfaro F, Marsili S, Cicero G, Bajardi E, Intrivici C, et al. Gemcitabine (GEM) plus oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX-4) in patients with advanced gastric cancer. Cancer Chemother Pharmacol 2005;56:563-8.  Back to cited text no. 7
8.Gagnadoux F, Roiron C, Carrie E, Monnier-Cholley L, Lebeau B. Eosinophilic lung disease under chemotherapy with oxaliplatin for colorectal cancer. Am J Clin Oncol 2002;25:388-90.  Back to cited text no. 8
9.Ramanathan RK, Clark JW, Kemeny NE, Lenz HJ, Gococo KO, Haller DG, et al. Safety and toxicity analysis of oxaliplatin combined with fluorouracil or as a single agent in patients with previously treated advanced colorectal cancer. J Clin Oncol 2003;21:2904-11.  Back to cited text no. 9
10.Pasetto LM, Monfardini S. Is acute dyspnea related to oxaliplatin administration? World J Gastroenterol 2006;12:5907-8.  Back to cited text no. 10
11.Garrido M, O'Brien A, Gonzalez S, Clavero JM, Orellana E. Cryptogenic organizing pneumonitis during oxaliplatin chemotherapy for colorectal cancer: Case report. Chest 2007;132:1997-9.  Back to cited text no. 11
12.Wilcox BE, Ryu JH, Kalra S. Exacerbation of pre-existing interstitial lung disease after oxaliplatin therapy: A report of three cases. Respir Med 2008;102:273-9.  Back to cited text no. 12
13.Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460-6.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]

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