Clinical features and correlates of gemcitabine-associated lung injury
Findings from the RADAR project
Gemcitabine is a commonly used chemotherapeutic agent structurally and pharmacologically similar to cytarabine. Recently, instances of severe gemcitabine-associated lung injury have been reported. Herein, investigators affiliated with the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program evaluated clinical characteristics of gemcitabine-associated severe acute lung injury from clinical trial reports, medical literature case reports, and spontaneous reports to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS).
Clinical data were obtained by reviewing adverse event case reports for gemcitabine-associated lung injury as reported in the medical literature and in the FDA AERS database. Upper limit estimates of ADE rate were derived from review of published clinical trials reporting gemcitabine-associated lung injury rates of 10% or higher.
A total of 178 reports of gencitabine-associated lung injury were identified; in AERS, there were 55 cases from clinical trials and 92 spontaneous reports. A comprehensive search revealed 31 medical literature reports. Clinical features of gemcitabine-associated lung injury included dyspnea, fever, pulmonary infiltrate, and cough with recognition of toxicity occurring after a median duration of 48 (range, 1-529) days after initiation of gemcitabine. The taxanes, docetaxel and paclitaxel, were frequently reported as coadministered therapies. Eleven Phase II or Phase III clinical trials with 317 patients identified gemcitabine-associated lung injury rates of greater than 10%, with the highest rates (22% and 42%) being observed in Phase III clinical trials where Hodgkin disease patients were treated with a regimen that included gemcitabine and bleomycin.
High rates of gemcitabine-associated severe lung injury were observed when gemcitabine was combined with other therapies known to also cause lung injury. Physicians should have a high index of suspicion for this toxicity and report the relevant clinical findings to the FDA's AERS. Cancer 2006. © 2006 American Cancer Society.
Gemcitabine, a cytotoxic deoxycytidine analog, was granted approval for marketing by the Food and Drug Administration (FDA) in 1996 for locally advanced or metastatic pancreatic cancer, and for a second indication in 1998 for use in combination with cisplatin for the treatment of locally advanced or metastatic nonsmall cell lung cancer. Gemcitabine is also widely used “off-label” in chemotherapeutic regimens for patients with other solid tumors and hematologic malignancies. Although gemcitabine has a broader spectrum of cytotoxic antitumor activity than cytarabine,1 the two drugs are structurally and pharmacologically similar.2, 3 Gemcitabine's cytotoxic activity is attributed to the synergistic effects of its diphosphate and triphosphate metabolites. Gemcitabine diphosphate inhibits ribonucleotide reductase, depleting dCTP formation and thereby enhancing incorporation of gemcitabine triphosphate into DNA, thus inhibiting DNA polymerase and RNA polymerase.
Mild hepatic transaminase elevation is the most common gemcitabine-associated toxicity, occurring in two-thirds of treated patients. Myelosuppression is the most common dose-limiting gemcitabine-associated toxicity. Mild, gemcitabine-associated dyspnea occurs in 25% of patients,4 but severe gemcitabine-associated acute lung injury has been reported only occasionally from initial clinical trials and more recently from spontaneous adverse drug event (ADE) reports submitted to the FDA's Adverse Event Reporting System (AERS) or to the pharmaceutical marketer. Recently, high rates of severe lung injury (22% to 42%) have been identified as the dose-limiting toxicity when gemcitabine-containing combination chemotherapeutic regimens were administered to persons with Hodgkin disease.5, 6
The purpose of postmarketing surveillance is to distinguish genuine ADE signals from the background noise of unrelated adverse events due to medical illness or other causes. For patients who receive gemcitabine in clinical trials, timely and prospective reporting of serious ADEs is mandatory and is transmitted in case report forms specifically designed for individual studies. Outside of the clinical trial setting, reporting of serious gemcitabine-associated ADEs such as acute lung injury is voluntary and generally transmitted as free-form case reports to the pharmaceutical manufacturer or to the FDA. To date, there has been no comprehensive study of the clinical features and correlates of gemcitabine-associated acute lung injury. The recently initiated Research on Adverse Drug Events and Reports (RADAR) project conducts detailed analyses of reports of chemotherapy-associated ADEs in cancer patients.7, 8 By reviewing all gemcitabine-associated pulmonary injury cases reported to the FDA's AERS and in the published literature, RADAR investigators had the unique opportunity to describe the frequency, severity, clinical features, and correlates of gemcitabine-associated lung injury.
MATERIALS AND METHODS
The RADAR project is a National Cancer Institute (NCI)-funded collaboration of oncologists, clinical pharmacologists, pharmacists, and statisticians affiliated with an NCI-designated comprehensive cancer center. The program is designed to identify and report on life-threatening or fatal cancer drug-associated ADE signals in both the clinical trial and nonclinical trial settings. RADAR investigators obtained case descriptions of gemcitabine-associated lung injury events reported either to the FDA's AERS or in the published literature (MeSH search terms were gemcitabine, interstitial pneumonitis, pulmonary infiltrates, pulmonary edema, noncardiac pulmonary edema, acute lung injury, congestive heart failure, acute respiratory distress syndrome, and capillary leak syndrome). AERS data were reviewed for the following information: initial date of adverse event reporting, pharmacovigilance program where the case was initially reported (pharmaceutical supplier or MedWatch), clinical trial setting (yes/no), and patient characteristics including sociodemographics, clinical and laboratory findings, types and dates of use of chemotherapeutic drugs and/or glucocorticosteroids, clinical evaluation of causality, treatment, and outcome. Information was collected through the use of a case report form developed specifically for gemcitabine-associated lung injury. The case definition included use of gemcitabine for anticancer chemotherapy and clinical findings, laboratory evidence, or imaging studies suggestive of pulmonary disease. Diagnostic methods included auscultation of the chest, cutaneous hemoglobin O2 saturation or arterial blood gas measurements, chest radiography, computerized tomography (CT) scans of the chest, and/or ventilation perfusion (V/Q) scans and bronchoscopy with or without biopsy or bronchoalveolar lavage. Clinical trial reports were also assessed for information on gemcitabine-associated lung injury incidence rates.
We abstracted data from ADE descriptions in published case reports, in clinical trial reports with severe acute lung injury rates of greater than 10%, and in spontaneous reports to the FDA's AERS program. Clinical data elements included sociodemographics (age, gender), days from initial administration of gemcitabine until onset of lung injury, clinical lung findings (dyspnea, cough, hypoxia), gemcitabine dose and dose schedule, imaging studies (roentgenogram, computerized axial tomography, nuclear ventilation/perfusion scan), pathology results from diagnostic studies (bronchoscopy, lung biopsy, autopsy), microbiology results (bronchoalveolar lavage, sputum Gram stain, sputum), indication of hospitalization or death, and clinician's assessment of relatedness of lung injury to gemcitabine exposure. Comparisons among the reporting sources were made using Fisher exact test for categorical attributes and optimal discriminant thresholds for ordered data, and were computed using Optimal Data Analysis statistical software.9
After eliminating duplicates and nulls, the AERS database included 178 reports of gemcitabine-associated lung injury from October 1 1997 through December 31 2003. Of these, 55 cases were reported by clinical trial investigators and 92 cases were voluntary MedWatch reports. A comprehensive literature search revealed 31 case reports of gemcitabine-associated lung injury from 1997 to 2004. Three MedWatch reports also described in detail in literature case reports were coded as “literature cases.”
Overall, 63% of patients were male, 32% were hospitalized, and 37% died. Concomitant cancer chemotherapy drugs or radiation therapy occurred significantly more often in clinical trial reports (82%) than in either AERS reports (50%), or literature case reports (29%) (Table 1). Hospitalization occurred in 94% of literature case reports, 74% of AERS reports, and 44% of clinical trial reports. Of the 170 patients for whom a cancer diagnosis was specified, the most common diagnoses were cancer of the lung (52%), pancreas (16%), and breast (6%). Of the 160 patients for whom clinical descriptions were in the ADE report, the most frequently reported were dyspnea (70%), fever (35%), pulmonary infiltrate (22%), and cough (19%) (Table 2). The most commonly mentioned coadministered chemotherapies were docetaxel (13%) and paclitaxel (13%) (Table 3). Concomitant radiation therapy was reported in 6% of patients. Recognition of severe acute lung toxicity occurred a median of 48 days (range, 1-529) after initiation of gemcitabine.
Table 1. Description of 178 Patients with Gemcitabine-Associated Lung Injury: Age, Gender, Dose, Bronchoscopy, Biopsy or Autopsy (Path), BAL, Cultures, Hospitalization, and Mortality
|Male||20 (65%)||35 (64%)||55 (60%)|| || || |
|Lung cancer||14 (45%)||33 (60%)||41 (45%)|| || || |
|Other ChemoRx/Rad Rx||9 (29%)||45 (82%)||46 (50%)||.0001|| ||.0002|
|Hospitalized||29 (94%)||24 (44%)||68 (74%)||.0001||.03||.0004|
|Died||9 (29%)||24 (44%)||32 (35%)|| || || |
|Age‡||62 12 60||62 12 64.5||60 12 62|| || || |
|Dose‡||1033 109 1000||1019 454 1000||983 167 1000||.02|| || |
|Days to onset||55 42 56||68 107 38.5||87 104 55|| || || |
Table 2. Clinical Findings Mentioned 5 or More Times in Reports of 160 Patients with Gemcitabine-Associated Pulmonary Toxicity for Whom Adverse Drug Event Descriptions Were Provided
|Chills or rigors||7||4.4|
Table 3. Coadministered Therapies (Drugs or Radiation) Mentioned 2 or More Times in Reports of 178 Patients with Gemcitabine-Associated Lung Injury
|Cisplatin||DNA Synthesis (varies by cell type)||13||7|
|Carboplatin||DNA synthesis (varies by cell type)||5||3|
Eleven Phase II or Phase III clinical trials involving a total of 317 patients identified gemcitabine-associated lung injury rates of 10% or greater (Table 4). The rate varied from 11% to 42%. The highest rate occurred in a trial where Hodgkin disease patients received multidrug chemotherapeutic regimens that included gemcitabine and bleomycin (Table 4).61
Table 4. Gemcitabine-Associated Severe Lung Injury in Selected Clinical Trials
|Friedberg et al.5||12||Hodgkin||Doxorubicin, bleomycin, vinblastine||42|
|Bredenfeld et al.6||27||Hodgkin||Bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone||22|
|Kourousis et al.57||26||Non-SCLC||Docetaxel||23|
|Popa et al.58||32||Non-SCLC||Docetaxel||19|
|Chen et al.59||40||Non-SCLC||Vinorelbine||15|
|Li et al.60||24||Bladder||Paclitaxel||14|
|Blackstock et al.61||16||Non-SCLC||Chest radiation||12|
|Safran et al.62||19||Pancreatic||Paclitaxel, radiation||11|
|Bhatia et al.63||34||Non-SCLC||Paclitaxel||10|
|Vokes et al.64||62||Non–SCLC||Cisplatin||23|
|Van Putten et al.65||25||Non-SCLC||Radiation||16|
This study describes the clinical features and correlates of gemcitabine-associated acute lung injury. Gemcitabine-associated severe acute lung injury was noted primarily in case reports of persons with cancer of the lung, breast, or pancreas or who had Hodgkin disease, occurring at a median interval of 48 days postinitiation of gemcitabine. Reports did not provide sufficient detail to reliably estimate the time interval between most recent gemcitabine dose and development of lung injury. Published clinical trial reports identified lung toxicity rates of 22% and 48% when persons with Hodgkin disease received combination chemotherapy regimens that included concomitant administration of gemcitabine and bleomycin.
Class effect considerations are often helpful in evaluating toxicities associated with new drugs. Because the structurally and pharmacologically related drug cytarabine has been in clinical use for more than two decades, the cytarabine toxicity experience is relevant. Over 80% of children10 or adults,11 given high-dose cytarabine develop a strong TNF-alpha response, triggering a cascade of proinflammatory cytokines (TNF-alpha, interferon-alpha, interleukin [IL]-1 alpha, and IL-6) and then an antiinflammatory cytokine counterresponse (IL-1ra, IL-10). Gemcitabine administration also induces release of proinflammatory cytokines in which the extent of TNF-alpha release is correlated with the severity of pulmonary and gastrointestinal toxicity.12 Moreover, in patients with gemcitabine-associated lung injury, several of the coadministered therapies are also known to induce or augment the proinflammatory cascade. Irradiation of the lung by itself induces a strong TNF-alpha response.13 Compared with lung irradiation and gemcitabine given alone, the combined effect of lung irradiation and gemcitabine in mice is synergistic, inducing lung tissue TNF-alpha mRNA levels 3-fold higher than would be expected from a simple additive effect.14 The vinca alkaloids, including vinorelbine, are known to induce release of IL-1 beta.15 Both carboplatin16 and cisplatin17 induce TNF-alpha release. Further, inhibition of TNF-alpha release by salicylates is protective against cisplatin-associated nephrotoxicity.17 Paclitaxel enhances TNF-alpha release triggered by other stimuli.18
Lung injury is a common complication of certain cancer chemotherapies, especially with drugs used at high doses or in conjunction with chest radiotherapy (Table 5). To date, the highest chemotherapy-associated lung injury rate, about 10%, is associated with bleomycin, with risk factors including high dosage and older patient age. Fatal pulmonary toxicity occurs in 1% of bleomycin-treated patients. Our review identifies a new chemotherapeutic agent, gemcitabine, as a drug that in certain circumstances can cause severe pulmonary injury. The highest rates of gemcitabine-associated toxicity ranged from 10% to 43%. Risk factors included concomitant administration of bleomycin, chemotherapeutic agents known to release cytokine mediators of inflammation such as vinorelbine, paclitaxel, or docetaxel, and concomitant use of chest radiotherapy. In most cases, lung injury resolved without specific treatment after discontinuation of gemcitabine, although in some cases resolution was attributed to treatment with either glucocorticosteroids or the combination of glucocorticosteroids and furosemide. Gemcitabine-induced cytokine release may potentiate the lung toxicity of coadministered drugs. Alternatively, coadministered drugs may augment gemcitabine-induced cytokine release or suppress the antiinflammatory counterresponse to gemcitabine-triggered cytokine release. Pharmacogenomic risk factors for gemcitabine-associated acute lung injury have not yet been fully characterized and may prove helpful in more precisely defining the population at risk.
Table 5. Pulmonary Syndromes Associated with Specific Cancer Chemotherapy Drugs
|Pulmonary capillary leak||Interleukin-2, recombinant tumor necrosis factor alpha, cytarabine, mitomycin|
|Asthma||Interleukin-2, vinca alkaloids plus mitomycin|
|Bronchiolitis obliterans organizing pneumonia||Bleomycin, cyclophosphamide, methotrexate, mitomycin|
|Hypersensitivity pneumonitis||Busulfan, bleomycin, etoposide, methotrexate, mitomycin, procarbazine|
|Interstitial pneumonia/fibrosis||Bleomycin, busulfan, chlorambucil, cyclophosphamide, melphalan, methotrexate, nitrosoureas, procarbazine, vinca alkaloids (with mitomycin)|
|Pleural effusion||Bleomycin, busulfan, interleukin-2, methotrexate, mitomycin, procarbazine|
|Pulmonary vascular injury||Busulfan, nitrosoureas|
The work described herein is one in a series of pharmaceutical postmarketing surveillance studies undertaken by the RADAR7 project. This team evaluates initial reports of serious ADEs, identifies additional reports, develops mechanistic hypotheses, evaluates related laboratory and pathologic findings, and derives reporting and incidence rate estimates.7 RADAR investigations have resulted in dissemination of our findings in the form of medical scientific publications, revised package inserts, and pharmaceutical manufacturers' “Dear Doctor” letters. This new, clinically based, hypothesis-driven approach to pharmaceutical postmarketing surveillance may supplement existing regulatory surveillance systems and improve patient safety.19
Our study has limitations. First, reporting bias is likely to exist. As is true for the safety database maintained by the manufacturer, the majority of gemcitabine-associated lung injury reports in this study are obtained from spontaneous reports and clinical trial ADE reports. These data sources make extensive use of free text fields to capture ADE descriptions. Development of syndrome-specific case report forms designed to capture key data elements and modeled after the NCI's CTCAE 3.0 would facilitate complete, accurate case reporting. This approach has proven useful in RADAR investigations of thalidomide-associate thromboembolism among persons with multiple myeloma, ticlopidine-associated20 and clopidogrel-associated21 thrombotic thrombocytopenic purpura, and erythroppoietin-associated pure red cell aplasia.22 Second, because clinicians rarely report ADEs that do not result in severe toxicity, it is not possible to evaluate the frequency with which mild, moderate, or severe cases of gemcitabine-associated lung injury occur from spontaneous ADE report databases. Among the cases in this database, one-third died from this toxicity. In 2005, the Cancer and Leukemia Group suspended accrual to a Phase II clinical trial study arm that included carboplatin and twice-weekly gemcitabine followed by conformal radiation therapy to the chest after 3 of 29 patients developed fatal radiation pneumonitis.23 In contrast, others have reported that gemcitabine-associated lung injury is usually self-limiting and often responsive to a glucocorticosteroid alone or a glucocorticosteroid plus a loop diuretic.24 Similarly, large randomized clinical trials in nonsmall cell lung cancer patients reported relatively low rates of pulmonary toxicity across arms that included gemcitabine and those that did not25; however, these trials did not include therapies identified in this study as being associated with high rates of pulmonary toxicity. Finally, the taxonomy of gemcitabine-induced lung injury is imperfect. Published literature reports describe apparently similar presentations of gemcitabine-associated lung injury with the terms capillary leak syndrome,24, 26–30 noncardiogenic pulmonary edema,16, 31, 32 interstitial pneumonitis,16, 33–48 acute pneumonitis,49 acute respiratory distress syndrome,8, 36, 50, 51 acute pulmonary toxicity,52 or acute lung injury.16, 44, 45, 36, 46, 53–56
In conclusion, our findings highlight the importance of consideration of the risk of lung injury from drug-drug or drug-radiotherapy interactions in designing novel therapeutic regimens for cancer patients, particularly for drugs with additive or synergistic pulmonary toxicity. The MedWatch program is the mechanism by which healthcare professionals and patients may report ADEs to the FDA. Oncologists may report chemotherapy drug-associated ADEs to the FDA's MedWatch program at www.fda.gov/medwatch. Heightened awareness of the potential for severe lung injury appears to be warranted when gemcitabine is concomitantly administered with bleomycin, docetaxel, paclitaxel, or radiation therapy.