Targ Oncol DOI 10.1007/s11523-014-0310-4
DAY-TO-DAY PRACTICE
Diagnostic challenges of respiratory adverse events during everolimus treatment Annelieke E. C. A. B. Willemsen & Filip Y. De Vos & Anne Jansen & Maaike de Boer & Vivianne C. G. Tjan-Heijnen & Carla M. L. van Herpen
Received: 11 September 2013 / Accepted: 18 February 2014 # Springer International Publishing Switzerland 2014
Abstract Everolimus has important clinical activity in various malignancies, but its use can be complicated by respiratory adverse events. Important everolimus-induced respiratory adverse events are interstitial lung disease (ILD) and infections, either typical or opportunistic. Furthermore, noneverolimus-related respiratory events can occur. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. Considering the potential fatal nature of opportunistic infections, these are especially important to recognize. To be able to distinguish between ILD and (opportunistic) infections as the underlying cause, an aggressive diagnostic workup, including bronchoalveolar lavage, should be performed in patients treated with everolimus who develop respiratory disease. We report three cases of severe opportunistic pulmonary infections during everolimus treatment, concerning two Pneumocystis jirovecii pneumonia infections. These cases illustrate the diagnostic challenges of respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.
A. E. C. A. B. Willemsen (*) : A. Jansen : C. M. L. van Herpen Department of Medical Oncology (452), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: [email protected] F. Y. De Vos Department of Medical Oncology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands M. de Boer : V. C. G. Tjan-Heijnen Division of Medical Oncology, Department of Internal Medicine, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
Keywords Everolimus . Pneumocystis jirovecii pneumonia . Pulmonary infection . Immunosuppression
Introduction Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a component of the intracellular PI3K/Akt signaling pathway that regulates cell proliferation, growth, metabolism, and angiogenesis [1]. Initially, everolimus was developed as immunosuppressive therapy for solid organ transplantation, as it inhibits the interleukin (IL)-2-stimulated T cell proliferation pathway [2]. Additionally, as a key regulator of cell growth and proliferation, mTOR is implicated in the pathogenesis of multiple malignancies. This resulted in the use of everolimus, in a much higher dose, as an anticancer agent for metastatic renal cell carcinoma (mRCC), for pancreatic neuroendocrine tumor, and in combination with exemestane for breast carcinoma [3–5]. Furthermore, everolimus is currently under investigation for the treatment of multiple other malignancies. The use of everolimus is, however, frequently complicated by adverse events. Among the most common adverse events, with an incidence of more than 10 %, are stomatitis, rash, fatigue, diarrhea, decreased appetite, and nausea. Respiratory adverse events occur frequently as well, with reported incidences in phase III trials of 20–30 % for cough, 18–24 % for dyspnea, 12–14 % for pneumonitis/interstitial lung disease (ILD), and 10 % for respiratory infections. These respiratory adverse events can even be fatal, as has been reported in cases of pneumonia, adult respiratory distress syndrome, candidial pneumosepsis, and bronchopulmonary aspergillosis [3, 5, 6]. Due to the immunosuppressive nature of everolimus, it is especially important to be aware of opportunistic infections, as these can be life-threatening if left untreated. This requires a specific diagnostic workup and treatment. Besides these
Targ Oncol
everolimus-induced disorders, respiratory symptoms have a broad further differential diagnosis, such as carcinomatous lymphangitis, congestive heart failure, pulmonary embolism, or radiation recall pneumonitis. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. In this report, we illustrate three cases of severe opportunistic respiratory infections during treatment with everolimus that demonstrate the diagnostic challenges of these respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.
Fig. 1 Patchy diffuse infiltrative changes in both lungs and left-sided pleural effusion
Case reports
Case B
Case A
A 51-year-old woman, known with estrogen receptor positive breast cancer with mediastinal and hilar lymph node metastases and carcinomatous pleuritis, started with everolimus and exemestane treatment after progression on letrozole. During treatment, she developed fever and dyspnea for which she was admitted to the hospital. Physical examination revealed a fever of 38.6 °C, a marked tachypnea of 36 per minute and dull percussion with diminished respiratory sounds over the left lower lung. Laboratory results showed a leukocyte count of 5.1x109/l, neutrophil count of 3.5x109/l, lymphocyte count of 1.0x109/l, monocyte count of 0.6x109/l, and C-reactive protein of 112 mg/l (normal range
DAY-TO-DAY PRACTICE
Diagnostic challenges of respiratory adverse events during everolimus treatment Annelieke E. C. A. B. Willemsen & Filip Y. De Vos & Anne Jansen & Maaike de Boer & Vivianne C. G. Tjan-Heijnen & Carla M. L. van Herpen
Received: 11 September 2013 / Accepted: 18 February 2014 # Springer International Publishing Switzerland 2014
Abstract Everolimus has important clinical activity in various malignancies, but its use can be complicated by respiratory adverse events. Important everolimus-induced respiratory adverse events are interstitial lung disease (ILD) and infections, either typical or opportunistic. Furthermore, noneverolimus-related respiratory events can occur. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. Considering the potential fatal nature of opportunistic infections, these are especially important to recognize. To be able to distinguish between ILD and (opportunistic) infections as the underlying cause, an aggressive diagnostic workup, including bronchoalveolar lavage, should be performed in patients treated with everolimus who develop respiratory disease. We report three cases of severe opportunistic pulmonary infections during everolimus treatment, concerning two Pneumocystis jirovecii pneumonia infections. These cases illustrate the diagnostic challenges of respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.
A. E. C. A. B. Willemsen (*) : A. Jansen : C. M. L. van Herpen Department of Medical Oncology (452), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: [email protected] F. Y. De Vos Department of Medical Oncology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands M. de Boer : V. C. G. Tjan-Heijnen Division of Medical Oncology, Department of Internal Medicine, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
Keywords Everolimus . Pneumocystis jirovecii pneumonia . Pulmonary infection . Immunosuppression
Introduction Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a component of the intracellular PI3K/Akt signaling pathway that regulates cell proliferation, growth, metabolism, and angiogenesis [1]. Initially, everolimus was developed as immunosuppressive therapy for solid organ transplantation, as it inhibits the interleukin (IL)-2-stimulated T cell proliferation pathway [2]. Additionally, as a key regulator of cell growth and proliferation, mTOR is implicated in the pathogenesis of multiple malignancies. This resulted in the use of everolimus, in a much higher dose, as an anticancer agent for metastatic renal cell carcinoma (mRCC), for pancreatic neuroendocrine tumor, and in combination with exemestane for breast carcinoma [3–5]. Furthermore, everolimus is currently under investigation for the treatment of multiple other malignancies. The use of everolimus is, however, frequently complicated by adverse events. Among the most common adverse events, with an incidence of more than 10 %, are stomatitis, rash, fatigue, diarrhea, decreased appetite, and nausea. Respiratory adverse events occur frequently as well, with reported incidences in phase III trials of 20–30 % for cough, 18–24 % for dyspnea, 12–14 % for pneumonitis/interstitial lung disease (ILD), and 10 % for respiratory infections. These respiratory adverse events can even be fatal, as has been reported in cases of pneumonia, adult respiratory distress syndrome, candidial pneumosepsis, and bronchopulmonary aspergillosis [3, 5, 6]. Due to the immunosuppressive nature of everolimus, it is especially important to be aware of opportunistic infections, as these can be life-threatening if left untreated. This requires a specific diagnostic workup and treatment. Besides these
Targ Oncol
everolimus-induced disorders, respiratory symptoms have a broad further differential diagnosis, such as carcinomatous lymphangitis, congestive heart failure, pulmonary embolism, or radiation recall pneumonitis. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. In this report, we illustrate three cases of severe opportunistic respiratory infections during treatment with everolimus that demonstrate the diagnostic challenges of these respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.
Fig. 1 Patchy diffuse infiltrative changes in both lungs and left-sided pleural effusion
Case reports
Case B
Case A
A 51-year-old woman, known with estrogen receptor positive breast cancer with mediastinal and hilar lymph node metastases and carcinomatous pleuritis, started with everolimus and exemestane treatment after progression on letrozole. During treatment, she developed fever and dyspnea for which she was admitted to the hospital. Physical examination revealed a fever of 38.6 °C, a marked tachypnea of 36 per minute and dull percussion with diminished respiratory sounds over the left lower lung. Laboratory results showed a leukocyte count of 5.1x109/l, neutrophil count of 3.5x109/l, lymphocyte count of 1.0x109/l, monocyte count of 0.6x109/l, and C-reactive protein of 112 mg/l (normal range
