|Ahead of print publication
Drug-induced infiltrative lung disease with weekly paclitaxel in breast cancer: Case series
Renu Raghupathi, Channappa Patil, Pravesh Dhiman
Department of Medical Oncology, Apollo Hospitals Bangalore, Bengaluru, Karnataka, India
Department of Medical Oncology, Apollo Hospitals, 154/11, Opp IIM Bannerghatta Road, Bangalore - 560 076, Karnataka
Source of Support: None, Conflict of Interest: None
Drug-induced infiltrative lung disease (DI-ILD) can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. Common chemotherapeutic drugs causing DI-ILD include bleomycin, mitomycin C, bis (2-chloroethyl)-l-nitrosourea, cyclophosphamide, busulfan, and methotrexate. Taxanes and trastuzumab are also associated with lung injury. Estimated incidence of paclitaxel-induced lung injury is 0.73%–12%. Although cases of paclitaxel-induced lung injury have been reported previously, we found only one published case report of fatal lung injury caused by paclitaxel use. We are reporting the largest case series of seven patients who developed paclitaxel-induced lung injury along with review of literature.
Keywords: Breast cancer, case series, chemotherapy, drug-induced infiltrative lung disease, paclitaxel
| > Introduction|| |
Drug-induced infiltrative lung disease (DI-ILD) can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs and immunosuppressive agents. The diagnosis of DI-ILD is a diagnosis of exclusion and usually involves three elements; clinical suspicion, exclusion of other parenchymal lung diseases using high-resolution computed tomography (HRCT) and other clinical tests (white blood cell count, sputum examination and culture, blood cultures, to rule out infections, electrocardiography, and echocardiography (ECHO) to exclude cardiac dysfunction, ventilation–perfusion scan if pulmonary embolism is suspected), and a compatible histological pattern. Drugs can induce alveolar filling processes, in addition to affecting the interstitium (ILD); hence, DI-ILD is a more comprehensive term. Common chemotherapeutic drugs causing DI-ILD include bleomycin, mitomycin C, bis (2-chloroethyl)-l-nitrosourea, cyclophosphamide, busulfan, and methotrexate.
Paclitaxel (taxol) is an anti-microtubule drug that is commonly used in the treatment of breast, ovarian and lung cancers. Common toxicities associated with paclitaxel include hypersensitivity reaction, peripheral neuropathy, myelotoxicity, and myalgia. DI-ILD (pneumonitis) is a very rare complication with paclitaxel. Its estimated incidence is 0.73%–12%.
Side effects of paclitaxel may be both dose-dependent and schedule-dependent, with increased risk for pulmonary toxicity with weekly or biweekly therapy compared to triweekly therapy and also with concurrent treatment with gemcitabine and irinotecan.
Trastuzumab which is often used with paclitaxel for the treatment of HER2/neu positive breast cancer patients has also been shown to cause pneumonitis. The incidence of trastuzumab-induced pneumonitis is 0.4%–0.6%. It may present as rapidly progressive pulmonary infiltrate with respiratory failure after the administration of 1 dose of trastuzumab or as a delayed manifestation up to 6 weeks of therapy. One case has been reported which has showed delayed development of interstitial pneumonitis after 9 weeks of treatment with weekly paclitaxel and trastuzumab.
Although a large number of cases of paclitaxel-induced lung injury have been reported previously, we found only one case reported of fatal lung injury caused by paclitaxel use. In contrast, trastuzumab-induced lung injury seems to be more severe with the mortality of trastuzumab-induced pneumonitis being about 0.1%. This may be attributed to the good response of paclitaxel-induced lung injury to treatment with steroids and discontinuation of the drug. This highlights the importance of having a high index of suspicion for drug-induced lung disease in patients being treated with paclitaxel, which is a potentially fatal complication.
We are reporting the largest case series of seven patients who developed paclitaxel-induced lung injury. All patients were diagnosed with carcinoma breast, with the youngest patient aged 32 years and the oldest patient aged 65 years. None of the patients had any predisposing respiratory disorders. Two patients had Stage III and IV disease (recurrence) each, whereas the other three patients had Stage II disease. All patients received treatment comprising paclitaxel 80 mg/m2 weekly. Two patients received concomitant 3 weekly trastuzumab with loading dose of 8 mg/kg and subsequent doses at 6 mg/kg. One patient received pertuzumab, loading dose of 840 mg followed by 420 mg, in addition to transtuzumab with paclitaxel. All patients presented with a clinical history of dry or productive cough, fever, and dyspnea, of varying severity. Two patients required intensive care unit admission with noninvasive ventilation support, three patients were admitted to the ward, and two patients were managed on outpatient department basis. ECHO ruled out cardiogenic pulmonary edema in all patients. HRCT thorax of all patients showed findings consistent with interstitial lung disease. All patients were treated with three doses of high-dose Solu-Medrol (500 mg) intravenous for 3 days. With treatment, they improved clinically and repeat imaging showed resolution of the pulmonary infiltrates. One patient was rechallenged with trastuzumab with no recurrence of symptoms [Table 1] and [Figure 1].
|Figure 2: Computed tomography chest showing recovery from drug-induced infiltrative lung disease after stopping paclitaxel and treatment with steroids|
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| > Discussion|| |
DI-ILD is the most common form of antineoplastic agent-induced respiratory disease. Several clinical syndromes have been described in patients with presumed antineoplastic agent-induced lung toxicity including acute and chronic manifestations such as bronchospasm, hypersensitivity reaction, infusion reaction, pneumonitis, noncardiogenic pulmonary edema, pulmonary edema, capillary leak syndrome, acute lung injury, acute respiratory distress syndrome (ARDS), and eosinophilic pneumonia.
The clinical manifestations of DI-ILD are nonspecific and include cough, fever, dyspnea, and hypoxemia. The pulmonary involvement may be rapidly progressive, resulting in respiratory failure and ARDS.
The mechanism of paclitaxel-induced hypersensitivity reactions remains unclear. It may be mediated by the release of histamines or other vasoactive substances like acute anaphylactic reactions, or it may result from a delayed hypersensitivity response. Although increased risk for pulmonary toxicity with weekly or biweekly therapy compared to triweekly therapy has been noted, there are no studies indicating any specific dose which is associated with higher toxicity.
DI-ILD is a diagnosis of exclusion, and other causes of respiratory failure including pneumonia, cardiogenic pulmonary edema, and diffuse alveolar hemorrhage should be excluded. Reduced lung volumes may be noted on pulmonary function testing. Bronchoalveolar lavage fluid may show elevated cell counts with neutrophilia, lymphocytosis, or rarely, eosinophilia.
Chest imaging findings include bilateral reticular or reticulonodular opacities, focal consolidation, and bilateral patchy areas of increased attenuation with the upper lobe predominance.
Two important points to note are that the timing of clinical manifestations is unpredictable; they may present during the first cycle of treatment or following subsequent cycles and also the treatment with corticosteroids as premedication may not prevent the development of drug-induced pneumonitis, although steroids play a crucial role in the subsequent treatment of drug-induced pneumonitis.
Interesting points noted in this case series were that etiology for all patients was breast cancer and all of them were on dose dense regimen of weekly 80 mg/m2 paclitaxel treatment. This indicates the need for further research to evaluate probable underlying risk factors and also studies to reassess the dose related to toxicity.
| > Conclusion|| |
ILD is a rare, but potentially fatal complication of paclitaxel treatment. Oncologists should keep this in mind while treating patients with paclitaxel and should pay careful attention to the clinical respiratory symptoms and radiographic findings of patients, Through out the period of treatment. Although diagnosing DI-ILD is difficult, it should be considered in all patients receiving chemotherapeutic agents presenting with clinical features consistent with the same as the cessation of paclitaxel and initiation of the early steroid therapy, as soon as paclitaxel-induced pneumonitis is suspected may result in rapid improvement.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]