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Journal of Clinical Oncology, Vol 24, No 33 (November 20), 2006: pp. 5330-5331 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.1083
Pneumocystis Carinii Pneumonia During Dose-Dense Chemotherapy for Breast CancerDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA A 52-year-old premenopausal woman with a T2N1 invasive ductal carcinoma of the right breast presented with fever and neutropenia. Two months before admission, she began chemotherapy with doxorubicin, 60 mg/m2, and cyclophosphamide, 600 mg/m2, given every 2 weeks, with pegfilgrastim support. She received antiemetics with each cycle that included 3 days of dexamethasone at 4 milligrams given twice daily. She received three cycles without difficulty, and before the fourth cycle, experienced a fever to 101.3°F accompanied by a nonproductive cough. She had no evidence of neutropenia, and her fevers resolved spontaneously, so she was treated with her fourth cycle. Three days after receiving her fourth cycle, she developed a fever, was evaluated as an outpatient, found to have a normal neutrophil count, and was discharged to home. A dry cough persisted, and 9 days after her fourth cycle of chemotherapy, she presented to an outside hospital with a fever and an absolute neutrophil count of 800/mm3. An initial chest x-ray was normal, and she was admitted and started on empiric ceftazidime, then cefipime, and then gatifloxacin and azithromycin, due to persistant fevers. A follow-up chest x-ray revealed infiltrates involving the left upper lobe, right upper lobe, and right lower lobe. Eighteen days after her fourth cycle of chemotherapy, she was transferred to our hospital for further evaluation. On admission, she was started on broad spectrum antibiotics with ceftazidime, vancomycin, and levoquin. A computed tomography scan of the chest revealed extensive air space opacification with air bronchograms and septal thickening (Fig 1). Nasal swabs were negative for adenovirus, influenza A and B, and respiratory syncytial virus, urine was negative for Legionella antigen, and serum was negative for parainfluenza antigen and Mycoplasma. An HIV antibody was negative, and a CD4 count was 485 mm3. She underwent bronchoscopy and bronchial alveolar lavage was positive for Pneumocystis carinii pneumonia (PCP). She was treated with bactrim and prednisone, and had improvement in her symptoms of shortness of breath, and a computed tomography scan of her chest showed resolution of the extensive air-space opacification.
PCP is predominantly seen in patients with AIDS, hematologic malignancies, and in transplant recipients. Cases of PCP in patients with breast cancer are rare, and previously described patients who developed PCP were receiving substantial corticosteroid therapy, or high-dose chemotherapy with peripheral blood stem-cell transplantation. We describe here the first reported case of PCP occurring in a patient receiving dose-dense every 2 week adjuvant chemotherapy, using doxorubicin and cyclophosphamide followed by paclitaxel. In the last year, we have had one other patient also develop PCP after her fourth cycle of dose-dense chemotherapy. PCP is a common opportunistic infection is those infected with HIV with CD4 counts less than 200 cells/mm3, but is less common in patients with cancer.1 In a retrospective review from Memorial Sloan-Kettering Cancer Center (New York, NY), the majority of cases of PCP were found in patients with hematologic malignancy.2 Corticosteriods are thought to be one of the strongest predisposing factors to the development of PCP in patients with cancer,3 with 87% of cases of PCP in this series occurring in patients receiving steroids. The median duration of therapy with corticosteroids before the onset of infection with PCP was about 12 weeks. Both of our patients had onset of symptoms approximately 8 weeks after initiating corticosteroids, which were given for several days at the beginning of each cycle of treatment. Most of the studies looking at the association of corticosteroid use and the risk of PCP involved continuous dosing of steroids, making it is difficult to know if the intermittent doses our patients received over four cycles placed them at risk for PCP. Reduced CD4 lymphocyte number is also thought to predispose patients to PCP.4,5 Lymphocyte depletion in patients receiving chemotherapy may correlate with the frequency and intensity of the dose.6 As the use of dose-intensive chemotherapy regimens has increased, there has been an increase in the incidence of opportunistic infections in patients with cancer.7 This suggests that the dose-intensive chemotherapy regimens, such as the dose-dense chemotherapy, may induce more frequent or severe lymphopenia. The use of filgrastim in the every 2-week dosing used in Cancer and Leukemia Group B trial 9741 results in a significant decrease in the incidence of grade 4 neutropenia and fewer treatment delays due to hematologic toxicity.8 More recently, it has become common to use pegfilgastrim in place of filgrastim because of the ease of administration and the apparent safety of the approach.9 While growth factor support has allowed for shorter intervals between cycles with adequate recovery of neutrophils, adequate lymphocyte reconstitution may not occur. When Mackall et al7 evaluated lymphocyte recovery in patients receiving dose-intensive chemotherapy, they found that lymphocyte populations did not recover before the administration of successive cycles of chemotherapy, despite having adequate recovery of neutrophils and platelets. This study involved too few patients to determine whether opportunistic complications directly correlated with the degree of lymphopenia. It has been suggested that the clinical course and outcome of PCP in patients with malignancy may be more fulminant than in patients with HIV, with mortality rates approaching 50%.2 In order to prevent PCP, some have recommended wider use of prophylaxis.10 In patients with malignancy, current recommendations are to give prophylaxis to those with acute lymphocytic leukemia, patients undergoing bone marrow transplantation, and those receiving corticosteroid therapy with Our two examples demonstrate that PCP can occur in patients receiving dose-dense chemotherapy for breast cancer. While dose-dense chemotherapy has been shown to improve disease-free and overall survival in those with node-positive breast cancer,13 further study is needed to investigate whether the shortened intervals between cycles may place patients at risk for lymphocyte depletion and increased incidence of opportunistic infections. Prospective assessment of the impact of dose-dense chemotherapy on lymphocyte counts and lymphocyte subsets is ongoing. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Sepkowitz KA: Opportunistic infections in patients with and patients without Acquired Immunodeficiency Syndrome. Clin Infect Dis 34 : 1098 -1107, 2002[CrossRef][Medline] 2. Sepkowitz KA, Brown AE, Telzak EE, et al: Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital. JAMA 267
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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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