A prospective study on lung toxicity in patients treated with gemcitabine and carboplatin: clinical, radiological and functional assessment

I. Dimopoulou1,*, E. Efstathiou2, A. Samakovli1, U. Dafni3, L. A. Moulopoulos4, C. Papadimitriou2, P. Lyberopoulos1, E. Kastritis2, C. Roussos1 and M. A. Dimopoulos2

1 Department of Pulmonary & Critical Care Medicine, Evangelismos Hospital, Athens; 2 Department of Clinical Therapeutics, Alexandra Hospital, Athens; Departments of 3 Biostatistics and 4 Radiology, Areteion Hospital, Medical and Nursing School, National & Kapodistrian University of Athens, Athens, Greece

* Correspondence to: Dr I. Dimopoulou, 2 Pesmazoglou Street, 14 561 Kifissia, Athens, Greece. Tel: +301-210-6200-663; Fax: +301-210-6202-939; Email: idimo{at}otenet.gr


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Small series and retrospective studies have suggested that treatment with gemcitabine may be associated with pulmonary toxicity. However, a prospective evaluation of cancer patients treated with gemcitabine-based chemotherapy without neoplastic involvement of the thorax and without administration of radiotherapy has not been performed.

Patients and methods: To investigate this issue, 41 consecutive patients receiving gemcitabine and carboplatin underwent prospective evaluation of lung function, which included pulmonary symptoms, pulmonary function tests, arterial blood gases and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with a substantial decline in diffusion capacity for carbon monoxide (DLCO), defined as a drop of ≥20%, were reassessed 2 months later.

Results: After chemotherapy, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, alveolar volume or total lung capacity. In contrast, there was a significant decline in DLCO (73±22 versus 67±24% predicted; P=0.017) and in carbon monoxide transfer coefficient (KCO) (89±24 versus 80±24% predicted; P=0.004). Arterial blood gases did not change following treatment. Ten of the 41 patients (24%) exhibited a substantial decline in DLCO, which, however, recovered within 2 months (DLCO at baseline, immediately after therapy and at 2 months after completion of treatment, 84±14, 58±16 and 77±17% predicted, respectively; P < 0.001; baseline DLCO versus DLCO at 2 months, P > 0.05). Four of the 41 patients (10%) experienced dyspnea, which was self-limiting, with the exception of one patient who developed interstitial lung fibrosis. Among the various risk factors examined, older age, female gender and lower baseline DLCO were associated with more profound changes in DLCO post-treatment.

Conclusions: This prospective analysis showed that the combination of gemcitabine and carboplatin induces a significant, but reversible, decrease in diffusion capacity, which is mostly asymptomatic. Thus, this regimen is safe as regards clinically significant lung toxicity.

Key words: carboplatin, diffusion capacity for carbon monoxide, dyspnea, gemcitabine, lung toxicity, pulmonary function tests


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Gemcitabine is a relatively new nucleoside analog that has emerged as a useful chemotherapeutic agent in the treatment of non-small-cell lung and pancreatic carcinomas. It is also active against breast, urothelial and ovarian cancer [1Go]. Thus, many patients are being exposed to this drug. Gemcitabine is generally well tolerated, and when adverse effects occur they consist of myelosuppression, flu-like symptoms, mild elevations in liver function tests, proteinuria–hematuria and peripheral edema [2Go].

Gemcitabine-related pulmonary toxicity has been reported in small series [3Go–7Go], retrospective studies [8Go] and review articles [9Go, 10Go]. Symptoms include primarily dyspnea and radiographic abnormalities consisting of interstitial infiltrates [3Go–10Go]. Pulmonary toxicity has been described when gemcitabine was used as a single agent [11Go, 12Go] or in combination with other chemotherapeutic drugs [13Go–15Go]. Proposed risk factors for lung toxicity include multimodality therapy with concurrent or prior irradiation to the chest [4Go, 8Go, 10Go, 16Go], and lung carcinoma [8Go, 9Go]. Pulmonary function tests (PFTs), which have been recommended for early detection of drug-associated pulmonary toxicity [17Go], before and following treatment with gemcitabine have received little systematic attention [8Go]. The potential of gemcitabine when administered alone or in combination with other drugs to induce lung toxicity in patients without neoplastic involvement of the thorax and without administration of radiotherapy has not been investigated prospectively.

In order to prospectively assess gemcitabine-induced lung toxicity, we designed a study that included patients treated with gemcitabine and carboplatin. Pulmonary function tests, clinical history, respiratory symptoms, lung examination, arterial blood gases and radiographic studies were obtained before and after completion of chemotherapy.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Patients eligible for the study included those who were treated with the combination of gemcitabine and carboplatin during the period October 2002 to December 2003. Each course consisted of gemcitabine administered at a dose of 1 g/m2 intravenously on days 1 and 8, and carboplatin administered at a dose of 5 or 6 AUC on day 1. Courses were repeated every 21 days, with dose adjustments according to toxicity. A standard premedication regimen with dexamethasone and ondasetron was used in all patients. Patients with primary lung cancer, metastatic disease in the thorax, prior chemotherapy or radiotherapy, recent (within 1 month) major surgery, presence of lung infection, or impaired performance status (Karnofsky performance status <80%) were excluded. The study was approved by the Institutional Review Board and all patients gave informed consent.

Clinical assessment
Before each course, physical examination was performed and the presence of respiratory symptoms such as cough, phlegm, wheezing or chest pain was recorded. Dyspnea was also evaluated and was expressed on a scale of 1 to 4: grade 0 none, grade 1 mild, grade 2 exertional dyspnea, grade 3 dyspnea at rest, grade 4 complete bed rest required.

Pulmonary function tests
Pulmonary function testing was performed 1–2 h before the administration of gemcitabine and carboplatin (first measurement). The second measurement was carried out within 14 days after completion of chemotherapy. The timing of the second measurement depended on the responsiveness of each patient to chemotherapy. Patients who did not benefit from treatment received as few as two courses, whereas those who demonstrated an objective response received as many as eight courses of chemotherapy. PFTs consisted of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV) and diffusion capacity for carbon monoxide (DLCO). Lung volumes were measured by the helium dilution method. DLCO was measured by the single-breath technique by determining alveolar volume (VA), and was corrected for the actual hemoglobin concentration [18Go]. Carbon monoxide transfer coefficient (KCO) was calculated as the ratio of DLCO/VA. All tests were performed with a Jaeger MasterScreen Diffusion system (E. Jaeger, Wuerzburg, Germany). Results of FVC, FEV1, TLC, FRC, RV, VA, DLCO and KCO are expressed as the percentage of predicted for each patient based on age, sex and height, whereas the ratio of FEV1/FVC is reported as an absolute percentage. Baseline PFTs were regarded as abnormal if the ratio of FEV1/FVC was <75% (obstruction), DLCO was <80% of predicted after correction for anemia (diffusion impairment) [19Go] or TLC was <80% of predicted (restriction) [20Go]. Changes in the PFTs values after chemotherapy were expressed as the difference between pre- and post-treatment values relative to the pretreatment values. Substantial declines in PFTs were defined as a reduction from a baseline in FEV1, TLC or DLCO of ≥20% [21Go–23Go]. Patients with a substantial drop in DLCO underwent additional PFTs 2 months after completion of chemotherapy (third measurement).

Arterial blood gases
On the same day as PFTs, arterial blood gases were obtained from the radial artery before chemotherapy (baseline) and at the end of treatment in all patients. In those who exhibited a significant decline in DLCO, a third sample was obtained 2 months following completion of all courses. Blood samples were analyzed for PaO2, PaCO2 and pH by an automated, computerized gas analyzer (Ciba Corning 238 pH/Blood Gas Analyzer; Ciba Corning Diagnostics Ltd, Halstead, UK).

Radiographic evaluation
All patients had chest radiographs performed prior to and following chemotherapy as part of the staging procedure. Patients who demonstrated a ≥20% post-treatment decline in DLCO underwent a high-resolution computed tomography (CT) scan of the thorax. Chest X-rays and CT scans were reviewed by a radiologist (L.A.M.), who was blinded to the results of the PFTs and to the clinical status of the patients. Radiographic evidence of toxicity was defined as the presence of new pulmonary interstitial or alveolar inflitrates on chest X-ray or CT scan in the absence of infection or metastatic disease to the thorax.

Data analysis and presentation
Data are expressed as mean±SD or as medians. Paired t-test or Wilcoxon signed rank test were used to analyze changes in PFTs, arterial blood gases and hemoglobin levels before and after chemotherapy. Repeated measures analysis of variance (ANOVA) was used to assess the evolution of DLCO and PaO2 over time, whereas Friedman repeated measures ANOVA on ranks was used to examine the trend of KCO. To isolate which groups differed from others, a multiple comparison procedure was used (Student–Newman–Keuls method). Factors of possible importance for a change in DLCO or KCO post-treatment, such as age, sex, smoking habits, baseline pulmonary function (FVC, FEV1, FEV1/FVC, TLC, DLCO, KCO), baseline PaO2 and cumulative dose of gemcitabine per m2, were entered into a multiple linear regression model and non-significant variables were deleted by backwards elimination (deletion criterion P > 0.05). A P value <0.05 was considered to be statistically significant. The SAS statistical package was used for analysis (SAS Institute Inc., Cary, NC, USA).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
During the study period, 52 patients receiving the combination of gemcitabine and carboplatin were eligble to enter the study. Of these, 11 patients were excluded for various reasons, including inability to perform PFTs (n=5), deterioration of the underlying malignancy (n=4), death (n=1) or because they were lost to follow-up (n=1). Thus, 41 patients participated in the current study, and their characteristics are presented in Table 1. Most patients were treated for bladder carcinoma. Patients received two to eight courses of chemotherapy. The median hemoglobin concentration before chemotherapy was 14.3 g/dl, and dropped to 13.5 g/dl post-treatment (P=0.002). The mean total dose of gemcitabin administered was 8.5±2.1 g/m2 (range 4–12.7).


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Table 1. Patient characteristics (n=41)

 
PFTs and arterial blood gases before and after chemotherapy
Before chemotherapy, mean or median values for flow rates, lung volumes, DLCO and KCO were within normal ranges (Table 2). However, a number of patients had isolated or combined pulmonary function abnormalities, including impairment in diffusion capacity (n=24), restriction (n=15) or obstruction (n=9). Mean PaO2 and PaCO2 before chemotherapy were normal. After completion of chemotherapy, which included two to eight courses, there were no significant changes in flow rates, lung volumes or arterial blood gases. In contrast, DLCO and KCO % predicted decreased significantly, by 6% and 9%, respectively (Table 2). Twelve patients developed isolated or combined substantial declines in PFTs, including a drop in DLCO (n=7) and in FEV1 (n=2), a decrease in FEV1 and in DLCO (n=2) and a decrease in TLC and in DLCO (n=1). Overall, substantial declines in DLCO and KCO were observed in 10 (24%) and 12 (29%) of the 41 patients, respectively. The final multiple regression analysis showed that the change in DLCO after therapy was associated with older age, female gender and lower baseline DLCO, whereas it was unrelated to smoking history, cumulative dose of gemcitabine, PaO2 or to any other PFTs (Table 3).


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Table 2. Pulmonary function tests and arterial blood gases at baseline and after chemotherapy with gemcitabine and carboplatin in all patients (n=41)

 

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Table 3. Factors contributing to a change in DLCO following therapy with gemcitabine and carboplatin

 
Respiratory symptoms and chest CT scans
At baseline, no patient had respiratory symptoms at rest or during exercise, and in particular, smokers with an obstructive ventilatory deffect on PFTs did not show a clinical pattern of chronic bronchitis. Four (10%) of the 41 patients developed grade 1 (n=1), grade 2 (n=2) or grade 4 (n=1) dyspnea between the second and the fourth course of chemotherapy. Of these four patients, three patients had a substantial decrease in DLCO and another patient had a decline of >20% in FEV1. No other respiratory symptoms were noted. Dyspnea resolved spontaneously in the three patients with grade 1–2, in whom no evidence of lung disease was evident on chest X-rays or CT scans. In contrast, symptoms deteriorated over time in the patient with grade 4 dyspnea, and his CT scan had findings consistent with interstitial lung fibrosis involving the middle and lower lobes. This patient was a 74-year-old smoker, who was treated for bladder carcinoma. His baseline FEV1 and TLC were normal, but pre-treatment DLCO was reduced (65% of the predicted value). His baseline PaO2 was 86 mmHg. He received six courses of gemcitabine, and the total dose administered was 11.1 g/m2. During chemotherapy he presented with grade 4 dyspnea, widespread inspiratory crackles on auscultation and exhibited a 28% drop in DLCO. By that time his arterial blood gases were PaO2 65 mmHg and PaCO2 31, pH 7.47. He was started on steroids and he experienced improvement in pulmonary symptoms. This patient died a few weeks later due to progression of bladder carcinoma.

Follow-up studies on patients with a substantial decline in DLCO
Of the 10 patients who exhibited substantial declines in DLCO immediately after chemotherapy, eight patients underwent a third lung function assessment (one patient died and another was unable to undergo assessment owing to deterioration of malignancy). Considering the eight patients as a group, it was noted that 2 months following completion of treatment, DLCO had partially recovered (DLCO at baseline, immediately after therapy and at 2 months after completion of treatment, 84 ± 14, 58 ± 16 and 77 ± 17% predicted, respectively; P < 0.001). DLCO at baseline was higher than DLCO post-therapy (P < 0.05); however, no significant difference was noted between baseline DLCO and DLCO at 2 months (P > 0.05). A similar trend was observed in median KCO (KCO at baseline, immediately after therapy and at 2 months after completion of treatment, 99, 67 and 98% predicted, respectively; P < 0.001). Baseline KCO was significantly higher than KCO post-treatment (P < 0.05), but KCO at 2 months did not differ from baseline KCO (P > 0.05). The oxygenation of the eight patients remained unchanged over time (PaO2 at baseline, immediately after therapy and at 2 months after completion of treatment, 84±10, 91±6 and 80±10 mmHg, respectively; P=0.07).


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The present study showed that acute, self-limiting pulmonary toxicity occurs in a relatively low percentage (10%) of patients treated with the combination of gemcitabine and carboplatin. In contrast, a significant subset (24%) of patients develop a clinically silent decrease in DLCO. A recovery of lung function impairment was documented 2 months after completion of chemotherapy. Among the risk factors evaluated, older age, female gender and lower baseline DLCO affected the trend of DLCO after treatment.

The frequency of gemcitabine-related pulmonary toxicity has been estimated to range from 2.7% [24Go] to 24% [25Go] in various analyses. Different clinical patterns have been described and include non-specific, self-limiting, exertional dyspnea occurring within days of therapy [11Go, 25Go], dyspnea along with infiltrates on chest X-ray reflecting non-specific interstitial pneumonitis [9Go, 13Go, 14Go], and dyspnea associated with bronchoconstriction responding to bronchodilators [25Go]. Less frequent entities consist of diffuse alveolar hemorrhage [26Go], pulmonary veno-occlusive disease [27Go], interstitial lung fibrosis [10Go, 16Go, 24Go] and acute respiratory distress syndrome [5Go]. Thus, a degree of lung dysfunction does occur following treatment with gemcitabine. Most reports have described this toxicity as mild and reversible [7Go, 11Go, 13Go, 25Go], but cases of fatal lung injury have also been reported [3Go, 5Go, 9Go, 12Go, 14Go, 24Go]. Gemcitabine shares close structural features to cytosine arabinosine, and the proposed mechanism of pulmonary injury in more serious cases is thought to represent a toxic damage on the endothelium of pulmonary capillary vessels causing leakage of the fluid, resulting in non-cardiogenic pulmonary edema [3Go]. Hypersensitivity reactions have also been implicated, because of the presence of pathologic inflammation and the improvement seen with steroid use [6Go, 7Go, 9Go, 11Go, 13Go, 28Go].

Information regarding the effects of gemcitabine on PFTs is sparse. Nowak et al. [15Go] enrolled 53 patients who were treated with cisplatin and gemcitabine for malignant mesothelioma. They showed that FVC and FEV1 improved significantly in responders and remained unchanged in non-responders. In that study, lung volumes and diffusion capacity were not measured. A recent retrospective analysis investigated 44 patients with advanced non-small-cell lung cancer who received gemcitabine and cisplatin followed by surgery and/or radiation. Lung toxicity was determined on the basis of radiological studies and lung function measurements. It was found that after treatment, KCO decreased significantly, by 13.5%, and that the main predictor for a decline in KCO was the pre-chemotherapy KCO, i.e. patients with higher baseline KCO showed greater changes in KCO after treatment than patients with lower baseline KCO. Similar results were obtained in their analysis when DLCO was considered [8Go]. Case studies reporting on patients with documented gemcitabine-induced pulmonary toxicity showed that a mild-to-moderate restrictive ventilatory defect and/or a reduction in DLCO may be present [3Go, 6Go, 7Go]. Furthermore, a substantial improvement in FVC and DLCO has been observed in a patient with gemcitabine-related dyspnea successfully treated with steroids [28Go].

To further clarify the magnitude of alterations in pulmonary function as a result of therapy with gemcitabine, we prospectively evaluated a group of patients with various malignancies. We excluded those with primary or metastatic lung cancer to avoid confusion from compromise in PFTs by the tumor itself. Although gemcitabine is frequently used in the treatment of several tumors, its administration as a single agent is limited. Thus, we decided to assess subjects receiving a combination of gemcitabine and carboplatin for two reasons: first, this combination is increasingly being used in patients with a broad range of tumor types [1Go]; secondly, and of paramount importance for the purpose of our study, it is well known that although carboplatin can cause hypersensitivity reactions [29Go], this drug lacks pulmonary toxicity, even when it used in conjunction with irradiation [30Go]. Contrary to most previous studies, our investigation examined the possibility of gemcitabine–carboplatin-induced lung toxicity on the basis of respiratory symptoms, radiological findings, arterial blood gases and, particularly, on the basis of PFTs. In line with other authors [8Go, 23Go], we showed that chemotherapy primarily affected diffusion capacity, whereas lung volumes or airflows did not change. Both VA and FVC remained unaltered by treatment, suggesting that the decline in DLCO was not due to an inadequate patient effort during performance of the maneuvers. We also demonstrated that older patients were more prone to develop pulmonary toxicity. This is in accordance with the results of others reporting on the toxicity of bleomycin, and could be explained by the fact that a decrease in the antioxidant defense system effectiveness may occur with age [17Go]. Furthermore, in our study patients with lower baseline DLCO levels showed greater changes in DLCO post-treatment. This is rather logical, and suggests that patients with a diminished lung function reserve should be closely monitored for potential pulmonary toxicity. On the other hand, this finding is in contradiction to a recent study, which showed that patients with a higher baseline DLCO exhibited more profound changes in post-therapy DLCO [8Go]. The reason for this discrepancy is unclear; differences between the two studies regarding the treatment modalities and/or patient characteristics, in particular baseline PFTs, could be possible explanations. Despite the changes in lung function, the majority of our patients were asymptomatic, and only 10% developed mild dyspnea. With the exception of the patient who had radiological findings on chest CT scan consistent with interstitial lung fibrosis, our study does not provide an explanation of the pathogenesis of gemcitabine-related lung toxicity. Dyspnea was self-limiting, DLCO recovered within 2 months after completion of chemotherapy and radiological findings were absent, indicating that hypersensitivity lung disease may be a potential mechanism [17Go]. This is further supported by the observation that a number of our patients with a substantial decrease in DLCO had a concurrent decline in FEV1, suggesting a degree of airway alteration.

The limitations of our study should be acknowledged. Patients without a decline in DLCO during the second measurement did not undergo further pulmonary function testing. Thus, we cannot rule out the possibility that late lung toxicity might have occurred.

In conclusion, the combination of gemcitabine and carboplatin induces a significant decrease in diffusion capacity. This lung function impairment is short-lasting and only occasionally associated with respiratory symptoms, which are usually mild and self-limiting. Taken together, our results suggest that this regimen is reliable in terms of a lack of respiratory complications.

Received for publication February 1, 2004. Revision received March 29, 2004. Accepted for publication March 29, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Carmichael J. The role of gemcitabine in the treatment of other tumours. Br J Cancer 1998; 78 (Suppl 3): 21–25.

2. Tonato M, Mosconi AM, Martin C. Safety profile of gemcitabine. Anticancer Drugs 1995; 6 (Suppl 6): 27–32.[ISI][Medline]

3. Pavlakis N, Bell DR, Millward MJ, Levi JA. Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 1997; 80: 286–291.[CrossRef][ISI][Medline]

4. Sauer-Heilborn A, Kath R, Schneider CP, Hoffken K. Severe non-haematological toxicity after treatment with gemcitabine. J Cancer Res Clin Oncol 1999; 125: 637–640.[CrossRef][ISI][Medline]

5. Dunsford ML, Mead GM, Bateman AC et al. Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma. Ann Oncol 1999; 10: 943–947.[Abstract]

6. Boiselle PM, Morrin MM, Huberman MS. Gemcitabine pulmonary toxicity: CT features. J Comput Assist Tomogr 2000; 24: 977–980.[CrossRef][ISI][Medline]

7. Joerger M, Gunz A, Speich R, Pestalozzi BC. Gemcitabine-related pulmonary toxicity. Swiss Med Wkly 2002; 132: 17–20.[ISI][Medline]

8. Maas KW, van der Lee I, Bolt K et al. Lung function changes and pulmonary complications in patients with stage III non-small cell lung cancer treated with gemcitabine/cisplatin as part of combined modality treatment. Lung Cancer 2003; 41: 345–351.[CrossRef][ISI][Medline]

9. Gupta N, Ahmed I, Steinberg H et al. Gemcitabine-induced pulmonary toxicity. Case report and review of the literature. Am J Clin Oncol 2002; 25: 96–100.[CrossRef][ISI][Medline]

10. Roychowdhury DF, Cassidy CA, Peterson P, Arning M. A report on serious pulmonary toxicity associated with gemcitabine-based therapy. Invest New Drugs 2002; 20: 311–315.[CrossRef][ISI][Medline]

11. Zatloukal P, Kanitz E, Magyar P et al. Gemcitabine in locally advanced and metastatic non-small cell lung cancer: the Central European phase II study. Lung Cancer 1998; 22: 243–250.[CrossRef][ISI][Medline]

12. Hoang T, Kim K, Jaslowski A et al. Phase II study of second-line gemcitabine in sensitive or refractory small cell lung cancer. Lung Cancer 2003; 42: 97–102.[CrossRef][ISI][Medline]

13. Chen YM, Perng RP, Yang KY et al. A multicenter phase II trial of vinorelbine plus gemcitabine in previously untreated inoperable (stage IIIB/IV) non-small cell lung cancer. Chest 2000; 117: 1583–1589.[Abstract/Free Full Text]

14. Bhatia S, Hanna N, Ansari R et al. A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non-small cell lung cancer. Lung Cancer 2002; 38: 73–77.[CrossRef][ISI][Medline]

15. Nowak AK, Byrne MJ, Williamson R et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002; 87: 491–496.[CrossRef][ISI][Medline]

16. Blackstock AW, Lesser GJ, Fletcher-Steede J et al. Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2001; 51: 1281–1289.[CrossRef][ISI][Medline]

17. Cooper JAD, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: cytotoxic drugs. Am Rev Respir Dis 1986; 133: 321–340.[ISI][Medline]

18. American Thoracic Society. Single-breath carbon monoxide diffusion capacity (transfer factor). Recommendations for a standard technique–1995 update. Am J Respir Crit Care Med 1995; 152: 2185–2198.[ISI][Medline]

19. American Thoracic Society. Evaluation of impairment/disability secondary to respiratory disorders. Am Rev Respir Dis 1986; 133: 1205–1209.[ISI][Medline]

20. Hughes JMB. Presentation of pulmonary function test to the clinician. In Hughes JMB, Pride NB (eds): Lung Function Tests: Physiological Principles and Clinical Applications, 1st edition. London: W.B. Saunders 1999; 287–295.

21. Castro M, Veeder MH, Mailliard JA et al. A prospective study of pulmonary function in patients receiving mitomycin. Chest 1996; 109: 939–944.[Abstract/Free Full Text]

22. Cottin V, Tebib J, Massonnet B et al. Pulmonary function in patients receiving long-term low-dose methotrexate. Chest 1996; 109: 933–938.[Abstract/Free Full Text]

23. Dimopoulou I, Galani H, Dafni U et al. A prospective study of pulmonary function in patients treated with paclitaxel and carboplatin. Cancer 2002; 94: 452–458.[CrossRef][ISI][Medline]

24. Takada M, Negoro S, Kudo S et al. Activity of gemcitabine in non-small-cell lung cancer: results of the Japan gemcitabine group (A) phase II study. Cancer Chemother Pharmacol 1998; 41: 217–222.[CrossRef][ISI][Medline]

25. Sorensen JB, Bergman B, Nielsen AL et al. Phase II study of gemcitabine and vindesine in patients with previous untreated non-resectable non-small-cell lung cancer. Br J Cancer 1999; 79: 875–881.[CrossRef][ISI][Medline]

26. Carron PL, Cousin L, Caps T et al. Gemcitabine-associated diffuse alveolar hemorrhage. Intensive Care Med 2001; 27: 1554.[CrossRef][ISI][Medline]

27. Vansteenkiste JF, Bomans P, Verbeken EK et al. Fatal pulmonary veno-occlusive disease possibly related to gemcitabine. Lung Cancer 2001; 31: 83–85.[CrossRef][ISI][Medline]

28. Vander Els NJ, Miller V et al. Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy. Chest 1998; 114: 1779–1781.[Abstract/Free Full Text]

29. Markman M, Kennedy A, Webster K et al. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 1999; 17: 1141–1145.[Abstract/Free Full Text]

30. Groen HJM, Van der Mark TW, Van der Leest AHD et al. Pulmonary function changes in lung-cancer patients treated with radiation with or without carboplatin. Am J Respir Crit Care Med 1995; 152: 2044–2048.[Abstract]