J Cancer Res Clin Oncol (2011) 137:1469–1475 DOI 10.1007/s00432-011-1013-1
ORIGINAL PAPER
Interstitial lung disease associated with gemcitabine treatment in patients with non-small-cell lung cancer and pancreatic cancer Shigeki Umemura • Hiromichi Yamane • Toshimitsu Suwaki Tsutomu Katoh • Takuya Yano • Yasuhiro Shiote • Nagio Takigawa • Katsuyuki Kiura • Haruhito Kamei
•
Received: 19 June 2011 / Accepted: 18 July 2011 / Published online: 5 August 2011 Ó Springer-Verlag 2011
Abstract Purpose Although there are several reports concerning gemcitabine-induced interstitial lung disease (ILD), the risk factors for ILD are not well known. In addition, data comparing the incidence and pattern of ILD associated with gemcitabine treatment in patients with non-small-cell lung cancer (NSCLC) versus those with pancreatic cancer are scarce. Methods We reviewed clinical records of 118 patients treated with gemcitabine between November 2004 and November 2010. The radiographic findings and other relevant clinical data were reviewed to identify patients who had developed ILD associated with gemcitabine treatment. Results Out of these 118 patients, we identified 62 patients with NSCLC (group A) and 56 patients with pancreatic cancer (group B), which were then analysed. After gemcitabine administration, ILD was detected in 9
S. Umemura (&) H. Yamane Y. Shiote H. Kamei Department of Clinical Oncology, Sumitomo Besshi Hospital, 3-1 Ohji-cho, Niihama 792-8543, Japan e-mail:
[email protected] S. Umemura T. Suwaki Y. Shiote H. Kamei Department of Respiratory Medicine, Sumitomo Besshi Hospital, Niihama, Japan T. Katoh Department of Radiology, Sumitomo Besshi Hospital, Niihama, Japan T. Yano Department of Pharmacology, Sumitomo Besshi Hospital, Niihama, Japan N. Takigawa K. Kiura Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
out of the total 118 patients (7.6%). Three patients had grade 2 ILD and 6 patients had grade 3 ILD. Multivariate analysis revealed that prior thoracic radiotherapy (odds ratio: 26.3) and pre-existing pulmonary fibrosis (PF) (odds ratio: 6.5) were correlated with ILD occurrence, but the incidence of ILD was not different between groups A and B. The median dose of gemcitabine administered till the manifestation of ILD tended to be lower in group A than in group B. Conclusions Prior thoracic radiotherapy and pre-existing PF were correlated with higher ILD rate in gemcitabinetreated patients. ILD incidence did not differ between NSCLC and pancreatic cancer patients, which may be due to the differences in treatment strategy and tumour properties. Keywords Gemcitabine Interstitial lung disease Lung cancer Non-small cell Pancreatic cancer Chemotherapy
Introduction Gemcitabine inhibits DNA synthesis by incorporating its active form into DNA and also by inhibiting the enzymes ribonucleotide reductase and deoxycytidine monophosphate deaminase (Lorusso et al. 2005; Pavlakis et al. 1997). It is administered as a pro-drug that is phosphorylated by deoxycytidine kinase into its active diphosphorylated and triphosphorylated forms (Gupta et al. 2002). Gemcitabine has been widely used to treat solid tumours such as breast, colon, ovarian, pancreatic and non-small-cell lung cancers (NSCLCs) (Galva˜o et al. 2010; Takeda et al. 2009; Ohe et al. 2007; Crino` et al. 1999; Burris et al. 1997). Myelosuppression is the most common dose-limiting toxicity associated with gemcitabine therapy.
123
1470
Gemcitabine-induced interstitial lung disease (ILD) has been reported to occur in up to 13.8% of patients (Vahid and Marik 2008). Analysis of data from a large database revealed that the incidence of gemcitabine-induced pulmonary toxicity occurred occasionally, varying from 0.02 to 0.27% (Briasoulis and Pavlidis 2001; Roychowdhury et al. 2002). However, high rates of severe lung toxicity have been identified when combination chemotherapeutic regimens including gemcitabine were administered (Takeda et al. 2009; Belknap et al. 2006). Furthermore, gemcitabine and concurrent thoracic radiotherapy have been associated with a high incidence of severe pneumonitis (Arrieta et al. 2009; Blackstock et al. 2006). Thus, as per these reports, the incidence of ILD associated with gemcitabine treatment shows variation. Since, the knowledge about the association of ILD with gemcitabine comes mainly from case reports, the risk factors of ILD are not well known (Belknap et al. 2006). Gemcitabine not only plays a major role in chemotherapy for advanced pancreatic cancer but is also used widely as first- and second-line drug for the treatment for metastatic NSCLC (Ohe et al. 2007; Crino` et al. 1999; Burris et al. 1997). For appropriate drug selection and prediction of its toxicity, it is imperative to determine the risk factors for ILD associated with gemcitabine treatment. Comparison of the incidence and pattern of ILD in different types of cancers may provide new insights for elucidating the mechanisms responsible for its induction. Therefore, our aim in the present study was to determine the incidence and risk factors for occurrence of ILD in gemcitabine-treated patients suffering from NSCLC and pancreatic cancer.
J Cancer Res Clin Oncol (2011) 137:1469–1475
outcomes, diagnosed pre-existing lung conditions as pulmonary fibrosis (PF) and emphysematous change based on computed tomography (CT). Pre-existing PF was defined as bilateral symmetrical opacities having a predominantly basilar distribution with areas of apparently normal lung tissue or those exhibiting a honeycomb pattern. ILD was diagnosed by chest radiography and CT findings, which defined it as a diffuse ground-glass opacity, reticular shadow or consolidation without segmental distribution and honeycomb pattern without evidence of underlying heart disease, infection or lymphangitic carcinomatosis. Toxicity was graded by using the National Cancer Institute Common Terminology Criteria (NCI-CTC) for Adverse Events version 4.0 Statistical analysis Statistical analyses were conducted using SPSS version 11.0 (Chicago, IL). Univariate and multivariate analyses were performed using an unconditional logistic regression model that included potential risk factors linked to the ILD occurrence. The association between several clinical characteristics of NSCLC versus pancreatic cancer, and the difference in median total dose of gemcitabine administered between NSCLC and pancreatic cancer patients were analysed using Fisher’s exact test. P values less than 0.05 were considered statistically significant. Ethics and role of the funding source The study was approved by the institutional review board of our institution. We received no external funding for this study.
Methods Patients and treatment
Results
We retrospectively analysed medical records of 120 consecutive NSCLC and pancreatic cancer patients who had undergone gemcitabine therapy at the Sumitomo Besshi Hospital between November 2004 and November 2010. Among the 120 patients, 2 patients (1 with NSCLC and 1 with pancreatic cancer) were excluded due to the occurrence of pneumonitis associated with sequential treatment (thoracic radiotherapy and chemotherapy with S-1, respectively) after gemcitabine administration. Therefore, 118 patients were available for the analysis. Of these, there were 62 patients with NSCLC (group A) and 56 with pancreatic cancer (group B). The radiology reports and other relevant clinical data were reviewed to identify patients who had developed ILD after treatment with gemcitabine. One independent pulmonologist and 1 radiologist, all of which who did not know the patient
Patient characteristics
123
Table 1 summarizes characteristics of 118 patients. Preexisting PF was detected in 13 patients (11%; 9 and 4 patients in groups A and B, respectively), which were all diagnosed solely on the basis of chest CT as chest radiographs were not informative. Compared with group B, group A included relatively fewer female patients (16% vs. 32%), more patients with thoracic irradiation (11% vs. 2%), prior chemotherapy employing one or more regimens (58% vs. 4%), and pre-existing emphysematous changes (52% vs. 12%). Gemcitabine was administered at doses of 800–1,000 mg/m2 on days 1 and 8 or 1, 8 and 15, every 3–4 weeks. In 70 patients, gemcitabine was administered as monotherapy. In the other 45 patients, gemcitabine was
J Cancer Res Clin Oncol (2011) 137:1469–1475
1471
Table 1 Patient characteristics
Group A (NSCLC)
Group B (pancreatic cancer)
No. of patients
62
56
Age, yr, median (range)
69.5 (33–81)
66 (40–81)
\70
31 (50%)
32 (57%)
C70
31 (50%)
24 (43%)
Female
10 (16%)
18 (32%)
Male
52 (84%)
38 (68%)
0/1
44 (71%)
46 (84%)
2/3
15 (24%)
9 (16%)
3 (5%)
1 (2%)
0
26 (42%)
54 (96%)
C1
36 (58%)
2 (4%)
No
55 (89%)
55 (98%)
Yes
7 (11%)
1 (2%)
No
53 (85%)
52 (93%)
Yes
9 (15%)
4 (7%)
P valuea
0.465
Gender 0.052
Performance status
Unknown No. of prior chemotherapy regimens
0.259
\0.001
Prior thoracic radiotherapy 0.064
Pre-existing pulmonary fibrosis 0.248
Pulmonary emphysematous change No
30 (48%)
49 (88%)
Yes
32 (52%)
7 (12%)
\0.001
Gemcitabine combining regimen
a
Fisher’s exact test
Gemcitabine alone
15 (24%)
55 (98%)
Gemcitabine ? cisplatin Gemcitabine ? carboplatin
21 (34%) 22 (35%)
1 (2%) 0 (0%)
Gemcitabine ? docetaxel ? cisplatin
1 (2%)
0 (0%)
Gemcitabine ? vinorelbine
3 (5%)
0 (0%)
co-administered with platinum agents. In 4 patients, gemcitabine was administered with non-platinum agents, 3 with vinorelbine and 1 with docetaxel, but none of these 4 patients developed ILD associated with the other nonplatinum agent.
thrombocytopenia in the other. The median total dose administered in all patients of both groups was 7,500 mg/ m2. The number (%) of patients whose total gemcitabine dose was \7,500 mg/m2 was 44 (71.0%) and 15 (26.8%), in groups A and B, respectively (P \ 0.001).
Treatment compliance
ILD incidence and pattern
Table 2 shows group A (NSCLC) and B (pancreatic cancer)’s treatment compliance rates. For group A, the median total dose administered was 4,000 mg/m2 (range 800–21,000 mg/m2). Treatment was discontinued in 3 (4.8%) patients within the first cycle because of either disease progression (1 patient) or adverse events (2 patients: neutropenia in 1 and thrombocytopenia in the other). For group B, the median total dose administered was 16,250 mg/m2 (range 2,000–78,000 mg/m2). Treatment was discontinued in 2 (3.6%) patients within the first cycle because of adverse events: neutropenia in 1 and
In all 118 patients, ILD was detected in 9 (7.6%) patients after they received gemcitabine. The ILD incidence was not different between group A (n = 5, 8.1%) and group B (n = 4, 7.1%). The characteristics and clinical courses for the 9 representative patients are listed in Table 3. The first symptoms of ILD observed in most patients were dyspnoea and fever. In this set of 9 patients, chest CT scans revealed new diffuse interstitial changes in both lungs with groundglass opacity and/or consolidation. The severity of ILD according to the NCI-CTC for Adverse Events v4.0 was as follows: 2 and 3 patients with grades 2 and 3, respectively
123
1472
J Cancer Res Clin Oncol (2011) 137:1469–1475
Table 2 Treatment compliance Total dosea
Total
Group A (NSCLC)
Group B (pancreatic cancer)
Median (range)
7,500 (800–78,000)
4,000 (800–21,000)
16,250 (2,000–78,000)
\7,500 mg/m2
59
44
15
C7,500 mg/m2
59
18
41
a
Total gemcitabine dose administered
b
Fisher’s exact test
(group A), and 1 and 3 patients with grades 2 and 3, respectively (group B). All patients were treated with corticosteroid therapy; 8 patients responded to the treatment as assessed by subjective symptoms and radiological findings. There were no deaths associated with ILD. In all 118 patients, the median time for ILD manifestation from first administration of gemcitabine was 56 days (range, 25–104 days). (In groups A and B, the median times for ILD manifestation from first administration of gemcitabine were 43 and 77 days, respectively.) In 2 of 3 patients who showed ILD with prior thoracic irradiation, the interval between chest radiotherapy and first administration of gemcitabine was almost 1 year. In the 9 patients described in Table 3 who developed ILD, the median dose of gemcitabine administered till ILD manifestation was 6,000 mg/m2. The percentage of patients whose gemcitabine dose was \6,000 mg/m2 at
P valueb
\0.001
manifestation of ILD was 80% in group A versus 0% in group B (P = 0.048). Risk factors for developing ILD Table 4 displays the results of univariate analysis of risk factors for developing ILD. Prior thoracic radiotherapy (P = 0.005) and pre-existing PF diagnosed by chest CT (P = 0.041) were identified by univariate analysis as independent risk factors for ILD. Based on the results of the univariate analysis, a multivariate analysis was performed using three variables (prior thoracic radiotherapy, pre-existing PF, and age C 70). The results demonstrate that prior thoracic radiotherapy (odds ratio: 26.3, 95% confidence interval: 3.4–202.1, P = 0.002) and pre-existing pulmonary fibrosis (odds ratio: 6.5, 95% confidence interval: 1.1–38.1, P = 0.039) were independent variables
Table 3 Characteristics of 9 patients with interstitial lung disease Pt. no.
Diagnosis
Age
Sex
PSc
PFd
No. of Che
Prior TRTf
ILD grade
1
NSCLCa
76
M
2
No
1
Yes
3
56
800
2
NSCLCa
33
F
1
No
1
Yes
3
25
3,000
3
NSCLC
a
71
M
1
Yes
1
No
3
43
4
NSCLCa
75
M
1
Yes
1
No
2
82
5
NSCLCa
75
M
1
No
2
Yes
2
6
Pancreasb
76
F
1
No
0
No
7
Pancreasb
66
F
1
No
0
8
Pancreasb
78
M
2
Yes
9
b
76
M
2
No
Pancreas
Responsei
Early death
Yes
No
No
No*
4,000
Yes
No
6,000
Yes
No
26
2,000
Yes
No
3
98
7,000
Yes
No
No
2
57
6,000
Yes
No
0
No
3
104
12,000
Yes
No
0
No
3
53
6,000
Yes
No
* Cause of death: progressive disease a
Non-small-cell lung cancer
b
Pancreatic cancer
c
Performance status
d
Pre-existing pulmonary fibrosis
e
Number of prior chemotherapy regimen
f
Thoracic radiotherapy
g
Time to ILD from first administration of gemcitabine (days)
h
The median dose of gemcitabine administered till ILD manifestation (mg/m2)
i
Response to steroid therapy
123
Time to ILDg
Doseh
J Cancer Res Clin Oncol (2011) 137:1469–1475
1473
Table 4 Risk factors for the occurrence of interstitial lung disease No. of patients
Univariate analysis
Evaluable
With ILD (%)
118
9 (7.6)
62
5 (8.1)
56
4 (7.1)
\70 years
63
2 (3.2)
C70 years Gender
55
7 (12.7)
Female
28
3 (10.7)
Male
90
6 (6.7)
0–1
90
6 (6.7)
2–3
24
3 (12.5)
Total
P value
a
Multivariate analysis P valuea
OR (95% CI)
Tumour NSCLCb Pancreas
c
0.851
–
–
0.07
0.09
0.485
–
–
0.354
–
–
0.419
–
–
0.005
0.002
26.322 (3.429–202.056)
0.041
0.039
6.468 (1.098–38.106)
0.454
–
Age 5.191 (0.773–34.876)
Performance status
No. of prior chemotherapy regimens 0
80
5 (6.3)
31
38
4 (10.5)
Prior thoracic radiotherapy No Yes
110 8
6 (5.5) 3 (37.5)
Pre-existing pulmonary fibrosis No
105
Yes 13 Pulmonary emphysematous change
6 (5.7) 3 (23.1)
No
79
5 (6.3)
Yes
39
4 (9.3)
–
ILD interstitial lung disease, OR odds ratio, CI confidence interval a
Logistic regression model
b
Non-small-cell lung cancer
c
Pancreatic cancer
that correlated with increased risk of gemcitabine-associated ILD. Prior thoracic radiotherapy strongly correlated with ILD risk.
Discussion There are several reports of pulmonary toxicity due to usage of gemcitabine as a single agent (Pavlakis et al. 1997; Galva˜o et al. 2010; Vahid and Marik 2008; Belknap et al. 2006; Ko et al. 2008; Shaib et al. 2008) or in combination with other anti-neoplastic agents (Takeda et al. 2009; Esteban et al. 2008; Boeck et al. 2007; Czarnecki and Voss 2006). In the present study, we found a relatively high incidence of ILD (7.6%) in patients treated with gemcitabine compared to previous reports (Ohe et al. 2007; Crino` et al. 1999; Burris et al. 1997; Briasoulis and Pavlidis 2001;
Roychowdhury et al. 2002). We believe that the reason for this high incidence may be attributed to different patient backgrounds between the present and other studies. We also demonstrated that prior thoracic radiotherapy and preexisting PF were correlated with a higher ILD rate among patients treated with gemcitabine. Pre-existing PF has been reported to be the most significant risk factor for the development of ILD associated with anti-cancer agents (Kudoh et al. 2008). In previous clinical trials, patients with pre-existing PF were ineligible, and a sub-set of patients with risk factors for ILD was excluded. The patients in our study were treated with gemcitabine, and their incidence of pre-existing PF was 11.0%. In the current study, pre-existing PF was diagnosed solely on the basis of chest CT, because it was not detected by chest radiography, and its incidence was not different between NSCLC and pancreatic cancer patients. Clinicians
123
1474
should therefore pay close attention to gemcitabine-treated patients with PF, which is only detected by chest CT. Furthermore, thoracic radiation is thought to be an ILD risk factor (Vahid and Marik 2008; Belknap et al. 2006). Irradiation of the lung by itself induces a strong TNF-a response (Ru¨be et al. 2004a). Compared with lung irradiation and gemcitabine administration alone, the combined effect of lung irradiation and gemcitabine in mice is synergistic, inducing a threefold increase in lung tissue TNF-a mRNA levels than would be expected from a single additive effect (Ru¨be et al. 2004b). Concurrent radiotherapy with gemcitabine has been associated with excessive pulmonary toxicity (Arrieta et al. 2009). Therefore, it is widely known that concurrent radiotherapy with gemcitabine should not be used apart from a clinical trial. In our study, no patients received concurrent radiotherapy with gemcitabine, but the percentage of patients having a history of thoracic radiotherapy was 6.8%. Gemcitabine treatment may not be recommended, even if sufficient period is maintained between gemcitabine administration and radiotherapy. According to our results, radiation-induced lung damage may represent the greatest risk factor for ILD. It is possible that sequential chest radiotherapy following gemcitabine administration is not recommended due to the interaction between gemcitabine and radiation. In this study, a number of chemotherapeutic regimens used earlier did not affect the incidence of gemcitabineinduced ILD, which suggests that sequential administration of gemcitabine followed by treatment with other cytotoxic drugs may not incur a high risk for ILD. Gemcitabineassociated acute lung injury was noted primarily in cancers of the lung, breast or pancreas or in patients with Hodgkin disease, each occurring at a median interval of 48 days after initiation of gemcitabine (Belknap et al. 2006). In the present report, the median interval was 56 days, which is nearly consistent with other reports. Interestingly, in our study, there was no statistical difference in the ILD incidence between NSCLC and pancreatic cancer. This may be attributable to the difference in the total dose of gemcitabine administered to NSCLC and pancreatic cancer patients. In pancreatic cancer patients, the median dose administered was [16,000 mg/m2, which was significantly higher than that administered in NSCLC patients. Few therapeutic standards of care exist for advanced pancreatic cancer patients who have progressed following first-line treatment with a gemcitabine-based regimen, and hence, gemcitabine is typically administered to the maximum extent until disease progression. If a dose similar to that administered in patients with pancreatic cancer is administered to NSCLC patients, the incidence of ILD in NSCLC may rise. We note that the median gemcitabine dose administered up to the manifestation of ILD was lower in NSCLC
123
J Cancer Res Clin Oncol (2011) 137:1469–1475
patients. This may be attributable to differences in patient characteristics. In the NSCLC group, more patients with a history of thoracic irradiation were included than in the pancreatic cancer group. Gemcitabine-associated ILD may occur at a relatively lower dose with a background of prior thoracic irradiation. Only 8 patients (7 with NSCLC and 1 with pancreatic cancer) received thoracic radiation, and this result must be interpreted with caution. The other limitation of this study was that we did not diagnose ILD by lung biopsy. However, the radiographic findings and clinical course were highly consistent with drug-induced ILD. Our findings indicate that prior thoracic radiotherapy and pre-existing PF were associated with a higher rate of gemcitabine-associated ILD. We therefore recommend that physicians should be careful while using gemcitabine to treat patients with these two risk factors. ILD incidence did not differ between patients with NSCLC or pancreatic cancer, which might be due to the difference in treatment strategy and characteristics of the two tumours. Increased awareness of the incidence and risk factors of ILD associated with chemotherapeutic drugs may be helpful not only for preventing serious side effects but also for selecting appropriate chemotherapeutic regimen for improving survival. Conflict of interest
None.
References Arrieta O, Gallardo-Rinco´n D, Villarreal-Garza C, Michel RM, Astorga-Ramos AM, Martı´nez-Barrera L, de la Garza J (2009) High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin. J Thorac Oncol 4:845–852 Belknap SM, Kuzel TM, Yarnold PR, Slimack N, Lyons EA, Raisch DW, Bennett CL (2006) Clinical features and correlates of gemcitabine-associated lung injury: findings from the RADAR project. Cancer 106:2051–2057 Blackstock AW, Ho C, Butler J, Fletcher-Steede J, Case LD, Hinson W, Miller AA (2006) Phase Ia/Ib chemo-radiation trial of gemcitabine and dose-escalated thoracic radiation in patients with stage III A/B non-small cell lung cancer. J Thorac Oncol 1:434–440 Boeck S, Hausmann A, Reibke R, Schulz C, Heinemann V (2007) Severe lung and skin toxicity during treatment with gemcitabine and erlotinib for metastatic pancreatic cancer. Anticancer Drugs 18:1109–1111 Briasoulis E, Pavlidis N (2001) Noncardiogenic pulmonary edema: an unusual and serious complication of anticancer therapy. Oncologist 6:153–161 Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413
J Cancer Res Clin Oncol (2011) 137:1469–1475 Crino` L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, Della Giulia M, Gridelli C, Rossi A, Calandri C, De Marinis F, Noseda M, Tonato M (1999) Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 17:2081–2085 Czarnecki A, Voss S (2006) Pulmonary toxicity in patients treated with gemcitabine and a combination of gemcitabine and a taxane: investigation of a signal using postmarketing data. Br J Cancer 94:1759–1760 Esteban E, Villanueva N, Mun˜iz I, Ferna´ndez Y, Fra J, Luque M, Jime´nez P, Llorente B, Capelan M, Vieitez JM, Estrada E, Buesa JM, Jime´nez-Lacave A (2008) Pulmonary toxicity in patients treated with gemcitabine plus vinorelbine or docetaxel for advanced non-small cell lung cancer: outcome data on a randomized phase II study. Invest New Drugs 26:67–74 Galva˜o FH, Pestana JO, Capelozzi VL (2010) Fatal gemcitabineinduced pulmonary toxicity in metastatic gallbladder adenocarcinoma. Cancer Chemother Pharmacol 65:607–610 Gupta N, Ahmed I, Steinberg H, Patel D, Nissel-Horowitz S, Mehrotra B (2002) Gemcitabine-induced pulmonary toxicity: case report and review of the literature. Am J Clin Oncol 25:96–100 Ko E, Lee S, Goodman A (2008) Gemcitabine pulmonary toxicity in ovarian cancer. Oncologist 13:807–811 Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Ichinose Y, Tsuboi M, Yokota S, Nakagawa K, Suga M, Japan Thoracic Radiology Group, Jiang H, Itoh Y, Armour A, Watkins C, Higenbottam T, Nyberg F (2008) Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested casecontrol study. Am J Respir Crit Care Med 177:1348–1357 Lorusso D, Ferrandina G, Fruscella E, Marini L, Adamo V, Scambia G (2005) Gemcitabine in epithelial ovarian cancer treatment: current role and future perspectives. Int J Gynecol Cancer 15:1002–1013
1475 Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M (2007) Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: FourArm Cooperative Study in Japan. Ann Oncol 18:317–323 Pavlakis N, Bell DR, Millward MJ, Levi JA (1997) Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 15:286–291 Roychowdhury DF, Cassidy CA, Peterson P, Arning M (2002) A report on serious pulmonary toxicity associated with gemcitabine-based therapy. Invest New Drugs 20:311–315 Ru¨be CE, Rodemann HP, Ru¨be C (2004a) The relevance of cytokines in the radiation-induced lung reaction. Experimental basis and clinical significance. Strahlenther Onkol 180:541–549 (in German) Ru¨be CE, Wilfert F, Uthe D, Ko¨nig J, Liu L, Schuck A, Willich N, Remberger K, Ru¨be C (2004b) Increased expression of proinflammatory cytokines as a cause of lung toxicity after combined treatment with gemcitabine and thoracic irradiation. Radiother Oncol 72:231–241 Shaib W, Lansigan F, Cornfeld D, Syrigos K, Saif MW (2008) Gemcitabine-induced pulmonary toxicity during adjuvant therapy in a patient with pancreatic cancer. JOP 9:708–714 Takeda K, Negoro S, Tamura T, Nishiwaki Y, Kudoh S, Yokota S, Matsui K, Semba H, Nakagawa K, Takada Y, Ando M, Shibata T, Saijo N (2009) Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol 20:835–841 Vahid B, Marik PE (2008) Pulmonary complications of novel antineoplastic agents for solid tumors. Chest 133:528–538
123
