Tumori, 92: 542-544, 2006
FATAL INTERSTITIAL PNEUMONITIS ASSOCIATED WITH DOCETAXEL ADMINISTRATION IN A PATIENT WITH HORMONE-REFRACTORY PROSTATE CANCER Karl Leimgruber1, Rosa Negro2, Susanne Baier3, Bernadetta Moser4, Gerhard Resch5, Stefano Sansone1, Michele Adami1, Peter Zanon4, Claudio Graiff3, Eduard Egarter-Vigl2, and Christian J Wiedermann1 Departments of 1Internal Medicine, 2Pathology, 3Oncology, 4Critical Care Medicine, and 5Pulmology, S. Maurizio Central Hospital of Bolzano, Bolzano, Italy Taxanes are widely used chemotherapeutic agents with the potential to induce pulmonary injury through a variety of mechanisms. Patients receiving these agents are at risk of acute or subacute pulmonary damage. The case is presented of a 72-year-old man with hormone-refractory prostate cancer and weekly administration of 30 mg/m 2 docetaxel who developed subacute interstitial pneumonitis-related
pulmonary fibrosis after seven doses and died despite mechanical ventilation and high-dose corticosteroid treatment. Even though only a few cases of this adverse event have been reported in the literature, severe docetaxel-induced pulmonary toxicity needs to be considered in the differential diagnosis when such patients present with respiratory symptoms.
Key words: adverse event, chemotherapy, fibrosis, respiratory failure, taxane.
Introduction
Parenchymal lung toxicity in patients treated with docetaxel was not described until 2001, when hypersensitivity pneumonitis was diagnosed based on the clinical course, radiological findings, and exclusion of other possible resultant causes, including metastatic cancer, radiation pulmonary injury, infection, or connective tissue disease1. The occurrence of this complication in response to docetaxel, which may be life-threatening and refractory to high-dose corticosteroid therapy, was subsequently confirmed in additional case series2,3. In the treatment of androgen-independent prostate cancer, potential pulmonary toxicity may be increased when docetaxel is combined with the tumor angiogenesis inhibitor, thalidomide4, but pulmonary toxicity of docetaxel may also be seen in the treatment of prostate cancer with no thalidomide5. We report a patient with prostate cancer who developed a severe pneumonitis 8 weeks after initiating weekly docetaxel with no thalidomide or other combinatory agent. The initial presentation and natural history of this process are described. Case report
A 72-year-old man with hormone-refractory prostate carcinoma (Gleason score, 9) was enrolled in a singleagent docetaxel treatment protocol with 30 mg/m2 weekly. Pretreatment chest X-ray was normal; metastases were confined to the bone; his Eastern Cooperative Oncology Group performance status was 1 (he was restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature).
After being premedicated with intravenous H1 and H2 blockers, corticosteroids and antiemetics, he received the first dose of docetaxel, 30 mg/m2 (60 mg), over 1 hr in December 2004. The treatment was repeated weekly until February 2005. A total of 7 cycles (accumulating dose, 420 mg) was well tolerated, with no hematological or cutaneous toxicity or other type of acute hypersensitivity reaction. The patient’s total prostate-specific antigen levels had decreased from 27.9 ng/ml before therapy to 4.9 ng/ml; renal and liver function tests including aspartate aminotransferase, alanine aminotransferase, and total bilirubin were within normal limits. Chemotherapy was interrupted in February 2005 for of loss of appetite, and increasing weakness had developed. Four days later, 52 days after beginning chemotherapy, he presented to the emergency department with fever of 38.8 °C and dyspnea. Physical examination was normal. The leukocyte count was not elevated at 5,030/mm3; a blood gas obtained from the patient on supplemental nasal O2 demonstrated a pH of 7.465, pCO 2 36.2 mmHg, and pO 2 59.7 mmHg. On chest radiograph, diffuse bilateral interstitial infiltrates with confluence in mid to upper lungs were observed. Broad-spectrum antibiotics were instituted. Elevated body temperature normalized but dyspnea worsened. Computed tomography scan of the chest on day 11 after admission showed diffuse confluent infiltrates, with little of the lung being spared. Bronchoscopy and bronchial alveolar lavage were performed, and cultures obtained from bronchoalveolar lavage were negative for Pneumocystis carinii, cytomegalovirus, and common bacteria. Echocardiogram documented normal left and right ventricular function, and lower extremity Doppler
Correspondence to: Prof. Christian J. Wiedermann, MD, 2nd Division of Internal Medicine, Department of Medicine, Central Hospital of Bolzano, Lorenz Böhler Street 5, 39100 Bolzano, Italy. Tel +43-0471-908190; fax +43-0471-908303; e-mail
[email protected] Received February 2, 2006; accepted March 27, 2006.
SEVERE INTERSTITIAL PNEUMONITIS ASSOCIATED WITH DOCETAXEL
sonography failed to identify a thrombus. Prednisolone (1 mg/kg body weight) was initiated for suspected docetaxol-induced interstitial pneumonitis. Despite corticosteroid treatment and non-invasive ventilatory support, pulmonary function deteriorated, and he was transferred to the intensive care unit on day 31 after admission, intubated, and placed on mechanical ventilation. Serum troponins and electrocardiogram were normal. Vasopressor infusion was required for episodes of hypotension. Repeated bronchoalveolar lavage remained negative for cultures, thereby confirming non-bacterial pneumonitis. However, gas exchange
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steadily declined, and on day 39 after admission, he died of multiple organ failure. Postmortem examination of the lung showed severe inflammatory fibrosis as indicated by the pattern of obliteration of alveoli by fibrotic tissue and collapsed and compressed capillaries (Figure 1). Discussion
Suspected risk factors for paclitaxel lung toxicity are its dose and combination with other cytostatic drugs or radiotherapy6. Following administration of docetaxel, a similar
A
B
Figure 1 - Lung histology at autopsy showing thickening of the alveolar walls by fibrosis and interstitial inflammation. A) Medium power photomicrograph of hematoxylin-eosin stain demonstrating changes in proliferative late-stage alveolar damage with alveolar cell proliferation, interstitial lymphocytes and septal thickening. B) High power photomicrograph of Van Gieson stain showing dense interstitial collagen (arrows).
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presentation of lung toxicity has also been noted1-5. Patients treated with docetaxel developed interstitial pneumonitis within a few weeks of administration characterized by dyspnea, fever and respiratory failure. Many of the patients died and others required prolonged mechanical ventilation, despite administration of high-dose corticosteroids. Severe pulmonary toxicity has been documented in patients receiving docetaxel in combination with gemcitabine for the treatment of transitional cell bladder cancer7,8 or other cytostatic agents for prostate cancer9, as also when used alone in prostate or breast cancer3,10. Most recently, Urakami et al.11 reported on docetaxelbased chemotherapy as second-line treatment for paclitaxel-based, chemotherapy-resistant, hormone-refractory prostate cancer in a pilot study. The results of their small study on 15 patients have suggested that docetaxel may be active for heavily pretreated patients who are paclitaxel resistant. However, significant toxicities were seen including 1 case of fatal pneumonitis (6.7%), 4 cases with dyspnea (26.7%) and 5 cases with pleural effusion (33.3%). The patient presented here received docetaxel at 30 mg/m 2 as a single agent, with no prior chemotherapy, suggesting that severe pulmonary toxicity may develop independently. Hypersensitivity reactions are uncommon with docetaxel compared to paclitaxel. Merad et al.12 reported a case presenting transient pulmonary infiltrates after docetaxel which resolved with steroid administration and necessitated cessation of therapy. Our patient received premedication with steroids and histamine receptor blockers, which successfully prevented acute hypersensitivity reactions. Delayed-type pneumonitis nevertheless developed. High-dose corticosteroid treatment of pneumonitis was instituted only after successful exclusion of pulmonary infectious or other types of disease, 11 days following admission. Concomitant therapy included antibiotic coverage, fluconazole and thrombosis
K LEIMGRUBER, R NEGRO, S BAIER ET AL
prophylaxis with enoxaparin. Despite the treatment and mechanical ventilation, the patient died after another 4 weeks. Unlike transient pulmonary infiltrates after docetaxel administration, it has been reported that late onset of interstitial pneumonitis frequently leads to respiratory failure, and patients usually require mechanical ventilation. This severe complication has been described with weekly and 3-week cycles of docetaxel9,11. With docetaxel, severe pneumonitis has been documented in less than 20 patients including ours, and more than 10 of these cases were fatal1,3,9,11. The patient we describe received docetaxel as a single agent, had no pulmonary metastases and normal hepatic function at the time of treatment. He presented with fever, dyspnea, and diffuse lung infiltrates within less than 2 months of receiving weekly cycles of docetaxel. The symptoms developed acutely over about 10 days, progressed on empiric therapies, and culminated in prolonged respiratory failure requiring mechanical ventilation, and the patient died as a direct result. Despite the rapid clinical deterioration as seen in the present case, early detection of pneumonitis – with dyspnea as a chief complaint and high-resolution computerized tomography as a principal diagnostic tool – may be important for stopping further chemotherapeutic drug administration and initiating appropriate therapy. We confirm that interstitial pneumonitis is a complication of docetaxel therapy that may progress despite high-dose corticosteroid medication. Docetaxel is currently the standard first-line treatment for hormone-refractory prostate cancer and is intensively studied in the adjuvant setting. Patients receiving docetaxel are at risk of severe pulmonary damage, and taxane-induced pulmonary toxicity needs to be considered in the differential diagnosis when such patients present with respiratory symptoms.
References 1. Wang GS, Yang KY, Perng RP: Life-threatening hypersensitivity pneumonitis induced by docetaxel (taxotere). Br J Cancer, 85: 1247-1250, 2001. 2. Mileshkin L, Prince HM, Rischin D, Zimet A: Severe interstitial pneumonitis following high-dose cyclophosphamide, thiotepa and docetaxel: two case reports and a review of the literature. Bone Marrow Transplant, 27: 559-563, 2001. 3. Read WL, Mortimer JE, Picus J: Severe interstitial pneumonitis associated with docetaxel administration. Cancer, 94: 847-853, 2002. 4. Behrens RJ, Gulley JL, Dahut WL: Pulmonary toxicity during prostate cancer treatment with docetaxel and thalidomide. Am J Ther, 10: 228-232, 2003. 5. Figg WD, Arlen P, Gulley J, Fernandez P, Noone M, Fedenko K, Hamilton M, Parker C, Kruger EA, Pluda J, Dahut WL: A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. Semin Oncol, 28 (Suppl 15): 62-66, 2001. 6. Goldberg HL, Vannice SB: Pneumonitis related to treatment with paclitaxel. J Clin Oncol, 13: 534-535, 1995. 7. Dunsford ML, Mead GM, Bateman AC, Cook T, Tung K: Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic tran-
sitional cell carcinoma. Ann Oncol, 10: 943-947, 1999. 8. Androulakis N, Kouroussis C, Kakolyris S, Tzannes S, Papadakis E, Papadimitriou C, Geroyianni A, Georgopoulou T, Dimopoulou I, Souglakos J, Kotsakis A, Vardakis N, Hatzidaki D, Georgoulias V: Salvage treatment with paclitaxel and gemcitabine for patients with non-small-cell lung cancer after cisplatin- or docetaxel-based chemotherapy: a multicenter phase II study. Ann Oncol, 9: 1127-1130, 1998. 9. Morris MJ, Santamauro J, Shia J, Schwartz L, Vander Els N, Kelly K, Scher H: Fatal respiratory failure associated with treatment of prostate cancer using docetaxel and estramustine. Urology, 60: 1111, 2002. 10. Karacan O, Eyuboglu FO, Akcay S, Ozyilkan O: Acute interstitial pneumopathy associated with docetaxel hypersensitivity. Onkologie, 27: 563-565, 2004. 11. Urakami S, Yoshino T, Kikuno N, Imai S, Honda S, Yoneda T, Kishi H, Shigeno K, Shiina H, Igawa M: Docetaxel-based chemotherapy as second-line treatment for paclitaxel-based chemotherapy-resistant hormone-refractory prostate cancer: a pilot study. Urology, 65: 543-548, 2005. 12. Merad M, Le Cesne A, Baldeyrou P, Mesurolle B, Le Chevalier T: Docetaxel and interstitial pulmonary injury. Ann Oncol, 8: 191-194, 1997.
