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Journal of Clinical Oncology, Vol 24, No 12 (April 20), 2006: pp. 1952-1953 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.0023
Acute Lung Injury Associated With VinorelbineDivision of Hematology/Oncology, and Lung Transplantation Program, Division of Pulmonary and Critical Care Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL A 38-year-old female physician of African descent was diagnosed with hormone-receptor–negative, node-positive, locally advanced carcinoma of the right breast. Following neoadjuvant chemotherapy with doxorubicin and cyclophosphamide, she underwent mastectomy and axillary lymph node dissection. Subsequently, she received paclitaxel and radiation to the chest wall. All chemotherapy required growth factor support. She was free of disease for 3 years until multiple, predominantly left, pleural-based nodules and a left malignant pleural effusion developed. The right lung was relatively free of disease. Breast cancer recurrence was confirmed. After a successful left video-assisted thoracoscopic pleurodesis with talc, she received a series of systemic therapies. In sequence, these were capecitabine, canertinib, and cisplatin. On disease progression, treatment with vinorelbine 25 mg/m2 weekly was started. Growth factor support was required, as with all her prior chemotherapy programs. Nine vinorelbine treatments throughout a 12-week period were administered. Her concurrent medications were lansoprazole, transdermal fentanyl, filgrastim, and rofecoxib. On the day of the latest treatment, she was slightly dyspneic. This worsened progressively throughout the next 2 days, resulting in hospitalization in the medical intensive care unit. She was afebrile but hypoxemic, with oxygen saturation less than 80%, despite 100% oxygen supplementation. A chest radiograph revealed bilateral diffuse interstitial infiltrates (Fig 1). A computed tomography (CT) of the chest demonstrated right-side dominant diffuse ground-glass opacities and stable, previously demonstrated mediastinal lymphadenopathy (Fig 2). No infectious, tumor-related, embolic, or cardiac cause for the infiltrates was found after extensive work-up. Both an echocardiogram and an ECG were unremarkable. The patient required high-flow oxygen delivered by noninvasive positive-pressure ventilation and, subsequently, by facial mask. Prednisone 40 mg/d was started. Four days later, her oxygenation improved. She was discharged from the hospital with home oxygen therapy. A follow-up CT scan 10 days later, though improved, still revealed ground-glass opacities (Fig 3). After 1 month, she required no oxygen supplementation. At this time, the CT scan demonstrated a near complete resolution of the opacities (Fig 4). Prednisone was gradually tapered off. Throughout this, her metastatic disease remained stable. She received no intercurrent systemic cancer treatments during the period of resolution. Subsequently, she proceeded with docetaxel, gemcitabine, and low-dose doxorubicin plus cyclophosphamide, respectively, using continuous filgrastim support, with no recurrence of these infiltrates to date. Hypoxic lung injury during cancer therapy poses a serious problem. Multiple agents can be implicated. In this patient, vinorelbine most likely was the causative agent of the pulmonary findings. While filgrastim has been associated with hypoxemia during neutrophil recovery,1,2 the lack of temporal association, leukocytosis, or positive rechallenge during subsequent chemotherapy makes it an unlikely offender in this case. No other causes could be elucidated after extensive work-up, though remote history of radiotherapy to the chest wall may have been a sensitizing factor. In a pooled analysis of three large multicenter trials conducted in North America with vinorelbine (n = 327), dyspnea was reported in 5% of patients; in 3% it was severe.3 This complication may occur after either the first or subsequent treatments. In fact, it may manifest as late as on the tenth cycle of treatment.4,5 Potential risk factors include concomitant use of mitomycin-C and history of dyspnea from a previous infusion.5,6
Two types of respiratory distress associated with vinorelbine have been reported: acute and subacute. The acute form, typically associated with acute dyspnea, bronchospasm, fever, hypotension, and alveolar infiltrates, usually occurs within minutes after vinorelbine infusion.3,6 The subacute form, occurring hours to days after infusion, is marked by progressive dyspnea, diffuse interstitial infiltrates, and in rare cases, acute respiratory distress syndrome.7 Vinorelbine, a semisynthetic vinca alkaloid, interacts with tubulin. It causes imbalance between polymerization and depolymerization and leads to a disruption of microtubule assembly—an essential component of vascular permeability regulation.8 Microtubule inhibitors cause a dysfunctional actomyosin cytoskeleton, leading to endothelial cell barrier dysfunction, which is similar to the pathogenesis of many conditions such as sepsis and acute lung injury.8 After infusion, vinorelbine achieves much higher concentration in heart and lung tissues than in serum.9 In fact, rare cases of myocardial infarction have also been reported in association with vinorelbine.10,11 Treatment of acute lung injury associated with vinorelbine or other suspected chemotherapeutic agents is largely supportive, and most reports recommend the use of corticosteroids. Typically, respiratory distress associated with single-agent vinorelbine is followed by full recovery. This syndrome, as with other vinca alkaloids such as vinblastine, may result in chronic lung disease, especially when mitomycin-C was concurrently administered.12 After one episode of respiratory distress, re-treatment with vinorelbine may lead to a more severe reaction, though some investigators re-treated patients, noting only a mild reaction, using premedication with corticosteroids.3,6 Vinorelbine most likely was the causative agent in this patient, and while resulting in a critical situation, was associated with a full recovery. As the role for vinorelbine in solid tumors, including breast cancer, continues to expand, clinicians must be aware of this possible severe, albeit uncommon, pulmonary complication, and query patients regularly regarding dyspnea during chronic vinorelbine dosing. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Schilero GJ, Oropello J, Benjamin E: Impairment in gas exchange after granulocyte colony stimulating factor (G-CSF) in a patient with the adult respiratory distress syndrome. Chest 107:276-278, 1995 2. White K, Cebon J: Transient hypoxaemia during neutrophil recovery in febrile patients. Lancet 345:1022-1024, 1995[CrossRef][Medline] 3. Hohneker JA: A summary of vinorelbine (Navelbine) safety data from North American clinical trials. Semin Oncol 21:42-47, 1994 (suppl 10)[Medline] 4. Tassinari D, Sartori S, Gianni L, et al: Is acute dyspnoea a rare side effect of vinorelbine? Ann Oncol 8:503-504, 1997 5. Raderer M, Kornek G, Hejna M, et al: Acute pulmonary toxicity associated with high-dose vinorelbine and mitomycin C. Ann Oncol 7:973-975, 1996 6. Cattan CE, Oberg KC: Vinorelbine tartrate-induced pulmonary edema confirmed on rechallenge. Pharmacotherapy 19:992-994, 1999[Medline] 7. Kouroukis C, Hings I: Respiratory failure following vinorelbine tartrate infusion in a patient with non-small cell lung cancer. Chest 112:846-848, 1997 8. Birukova AA, Smurova K, Birukov KG, et al: Microtubule disassembly induces cytoskeletal remodeling and lung vascular barrier dysfunction: Role of Rho-dependent mechanisms. J Cell Physiol 201:55-70, 2004[CrossRef][Medline] 9. Leveque D, Quoix E, Dumont P, et al: Pulmonary distribution of vinorelbine in patients with non-small-cell lung cancer. Cancer Chemother Pharmacol 33:176-178, 1993[CrossRef][Medline] 10. Bergeron A, Raffy O, Vannetzel JM: Myocardial ischemia and infarction associated with vinorelbine. J Clin Oncol 13:531-532, 1995 11. Karminsky N, Merimsky O, Kovner F, et al: Vinorelbine-related acute cardiopulmonary toxicity. Cancer Chemother Pharmacol 43:180-182, 1999[Medline] 12. Rivera MP, Kris MG, Gralla RJ, et al: Syndrome of acute dyspnea related to combined mitomycin plus vinca alkaloid chemotherapy. Am J Clin Oncol 18:245-250, 1995[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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