Cancer Chemother Pharmacol (2014) 74:1159–1166 DOI 10.1007/s00280-014-2590-x
ORIGINAL ARTICLE
The safety and efficacy of paclitaxel and carboplatin with or without bevacizumab for treating patients with advanced nonsquamous non‑small cell lung cancer with interstitial lung disease Ryoko Shimizu · Daichi Fujimoto · Ryoji Kato · Takehiro Otoshi · Takahisa Kawamura · Koji Tamai · Takeshi Matsumoto · Kazuma Nagata · Kyoko Otsuka · Atsushi Nakagawa · Kojiro Otsuka · Nobuyuki Katakami · Keisuke Tomii
Received: 26 February 2014 / Accepted: 10 September 2014 / Published online: 23 September 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Optimal chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is established for paclitaxel and carboplatin, but is otherwise controversial. Therefore, we assessed the efficacy and safety of paclitaxel and carboplatin with or without bevacizumab for treating these patients. Methods We analyzed the outcomes of 21 patients with advanced nonsquamous NSCLC with ILD who received paclitaxel and carboplatin without (paclitaxel–carboplatin group; n = 11) or with bevacizumab (paclitaxel–carboplatin–bevacizumab group; n = 10) between April 2008 and October 2013. Results The median progression-free survival time of the paclitaxel–carboplatin–bevacizumab group was 5.3 months (95 % CI 0.4–11.6 months) compared with 4.4 months (95 % CI 0.9–6.3 months) for the paclitaxel–carboplatin group (p = 0.060). Their respective median overall survival times were 16.1 months (range 0.4–34.8 months) and 9.7 months (range 2.6–37.0 months) (p = 0.772) with corresponding overall response rates of 40 and 27 % (p = 0.659), respectively. One patient in the paclitaxel–carboplatin–bevacizumab group experienced chemotherapyrelated exacerbation of ILD (0/11 vs. 1/10; p = 0.476). Conclusions The addition of bevacizumab to paclitaxel and carboplatin may provide an effective and safe treatment R. Shimizu (*) · D. Fujimoto (*) · R. Kato · T. Otoshi · T. Kawamura · K. Tamai · T. Matsumoto · K. Nagata · K. Otsuka · A. Nakagawa · K. Otsuka · N. Katakami · K. Tomii Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2 Minatojima‑minamimachi, Chuo‑ku, Kobe 650‑0047, Japan e-mail: [email protected]; [email protected] D. Fujimoto e-mail: [email protected]
option for patients with advanced nonsquamous NSCLC with ILD. Keywords Chemotherapy-related exacerbation · Interstitial lung disease · Idiopathic pulmonary fibrosis · Non-small cell lung cancer · Usual interstitial pneumonia · Vascular endothelial growth factor
Introduction Lung cancer is the leading cause of cancer deaths worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 80 % of lung cancers, and the majority are unresectable and metastatic upon initial diagnosis. Cytotoxic platinum-based chemotherapy is the primary therapeutic option for metastatic NSCLC [2]. Evidence indicates that interstitial lung disease (ILD), which is also called diffuse parenchymal lung disease, is associated with lung carcinogenesis [3, 4]. Smokers with interstitial lung abnormalities in unselected populations are relatively common [5, 6]. In addition, the cumulative incidence of lung cancer in patients with idiopathic pulmonary fibrosis (IPF), which is the most common subset of ILD, increased at the rates of 3.3, 15.4, and 54.7 % over 1, 5, and 10 years, respectively [7]. Chemotherapy-related exacerbation of ILD ranges in incidence from 8.7 to 21 %, and it is a fatal complication of treatment of lung cancer [8, 9]. Cytotoxic chemotherapeutics such as gemcitabine and docetaxel induce severe exacerbation of ILD [10, 11]. In contrast, paclitaxel and carboplatin combination chemotherapy is effective and relatively safe for patients with advanced NSCLC with ILD [12, 13]. However, optimal chemotherapy using other agents has not been elucidated.
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Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), which significantly extends overall survival (OS) and progression-free survival (PFS), and it improves the overall response rate (ORR) of patients with advanced nonsquamous NSCLC when combined with paclitaxel and carboplatin [14]. The addition of bevacizumab does not increase the rate of chemotherapy-related pneumonitis; however, BIBF 1120, which inhibits the activities of multiple protein tyrosine kinases such as the VEGF receptor, shows potential for treating patients with IPF [15, 16]. Therefore, we hypothesized that paclitaxel and carboplatin together with bevacizumab may effectively and safely treat patients with advanced nonsquamous NSCLC with ILD. For this purpose, we conducted a retrospective study aimed to evaluate this hypothesis.
Patients and methods Patients We analyzed 21 patients with advanced nonsquamous NSCLC and ILD who received paclitaxel and carboplatin alone (paclitaxel–carboplatin group) or paclitaxel and carboplatin with bevacizumab (paclitaxel–carboplatin– bevacizumab group) at Kobe City Medical Center General Hospital between April 2008 and October 2013. Results were analyzed retrospectively using case and radiographic records. Patients who reported never smoking were designated never smokers, those who smoked within 1 year of the diagnosis were categorized as current smokers, and all others were designated former smokers. The Ethics Committee of Kobe City Medical Center General Hospital approved this study. Treatment Treatment regimens were as follows: (1) Paclitaxel–carboplatin group (PC group): Carboplatin every 4 weeks at a dose determined by the area under the curve (AUC) 4–5 was administered on day 1, and paclitaxel at a dose of 60–70 mg/m2 was administered on days 1, 8, and 15. Each 4-week treatment schedule was designated as one cycle. (2) Paclitaxel–carboplatin–bevacizumab group (PCB group): Carboplatin every 4 weeks at a dose of AUC 4–5 and bevacizumab at a dose of 15 mg/kg were administered on day 1 and paclitaxel at a dose of 70 mg/m2 was administered on days 1, 8, and 15. Each 4-week treatment schedule was designated as one cycle. None of the patients received maintenance chemotherapy or continued therapy beyond the Response Evaluation Criteria in Solid Tumors (RECIST) progression. None of the patients had a contraindication for
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Cancer Chemother Pharmacol (2014) 74:1159–1166
bevacizumab such as having a history of severe pulmonary hemorrhage, pulmonary cavitation, or tumor invasion of major blood vessels. After the PASSPORT study, patients with brain metastasis received the bevacizumab regimen after stereotactic radiotherapy or whole-brain radiotherapy, according to the result of that study [17]. Interstitial lung disease (ILD) Preexisting ILD was diagnosed according to clinical features and pretreatment chest high-resolution computed tomography (HRCT) results. All patients received HRCT according to standard clinical practice, and the presence of ILD was evaluated by at least two pulmonologists. We considered ILD into usual interstitial pneumonia (UIP) and non-UIP patterns. Diagnosis of UIP pattern was determined using CT features, defined by the International Consensus Statement of the American Thoracic Society and the European Respiratory Society, showing subpleural distribution, honeycombing (Fig. 1), traction bronchiectasis, and architectural distortion [18, 19]. Patients with ILD revealed by CT, except for those with the (UIP) pattern, were diagnosed with the non-UIP pattern. Chemotherapy-related exacerbation of ILD was diagnosed according to CT findings (bilateral ground-glass abnormality with or without focal consolidation superimposed on pretreatment interstitial shadow) [20]. We excluded patients with apparent pulmonary infection, pulmonary embolism, or heart failure. Chemotherapyrelated exacerbation of ILD was evaluated according to the presence of pneumonitis/pulmonary infiltrates by the United States National Cancer Institute Common Terminology Criteria version 3.0 as follows: Grade 3: symptomatic, interfering with activities of daily living, and oxygen indicated; Grade 4: life-threatening; and Grade 5: death. To assess the incidence of chemotherapy-related exacerbation of ILD, the duration between the last administration of cytotoxic chemotherapy and the onset of exacerbation of ILD was defined as 4 weeks or fewer. Patient evaluation and statistical analysis A CT scan was performed within 28 days before initiating treatment to assess the primary tumor and was repeated every 2–3 months. All responses were defined according to RECIST. A response was confirmed at least 4 weeks (for a complete or partial response) or 6 weeks (for stable disease) after the first documentation. PFS was measured from the start of treatment to the time of progression. OS was measured from the start of treatment until death by all causes. PFS and OS were determined using the Kaplan– Meier method. The log-rank test was used to compare the cumulative survival of each group. Continuous variables were analyzed using the Student’s t test, and the results
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Fig. 1 HRCT image of the chest. a Subpleural distribution, honeycomb cysts, and bronchiectasis (UIP pattern). b Patchy ground-glass opacity with reticulation, traction bronchiectasis, and bronchovascular bundle thickening (non-UIP pattern)
were expressed as the mean ± standard deviation (SD). Dichotomous variables were analyzed using the Chi-square test or the Fisher’s exact test, as appropriate. The relationship between numerical and categorical variables was compared using the Wilcoxon signed-rank test. All tests were two-tailed, and p
ORIGINAL ARTICLE
The safety and efficacy of paclitaxel and carboplatin with or without bevacizumab for treating patients with advanced nonsquamous non‑small cell lung cancer with interstitial lung disease Ryoko Shimizu · Daichi Fujimoto · Ryoji Kato · Takehiro Otoshi · Takahisa Kawamura · Koji Tamai · Takeshi Matsumoto · Kazuma Nagata · Kyoko Otsuka · Atsushi Nakagawa · Kojiro Otsuka · Nobuyuki Katakami · Keisuke Tomii
Received: 26 February 2014 / Accepted: 10 September 2014 / Published online: 23 September 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Optimal chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is established for paclitaxel and carboplatin, but is otherwise controversial. Therefore, we assessed the efficacy and safety of paclitaxel and carboplatin with or without bevacizumab for treating these patients. Methods We analyzed the outcomes of 21 patients with advanced nonsquamous NSCLC with ILD who received paclitaxel and carboplatin without (paclitaxel–carboplatin group; n = 11) or with bevacizumab (paclitaxel–carboplatin–bevacizumab group; n = 10) between April 2008 and October 2013. Results The median progression-free survival time of the paclitaxel–carboplatin–bevacizumab group was 5.3 months (95 % CI 0.4–11.6 months) compared with 4.4 months (95 % CI 0.9–6.3 months) for the paclitaxel–carboplatin group (p = 0.060). Their respective median overall survival times were 16.1 months (range 0.4–34.8 months) and 9.7 months (range 2.6–37.0 months) (p = 0.772) with corresponding overall response rates of 40 and 27 % (p = 0.659), respectively. One patient in the paclitaxel–carboplatin–bevacizumab group experienced chemotherapyrelated exacerbation of ILD (0/11 vs. 1/10; p = 0.476). Conclusions The addition of bevacizumab to paclitaxel and carboplatin may provide an effective and safe treatment R. Shimizu (*) · D. Fujimoto (*) · R. Kato · T. Otoshi · T. Kawamura · K. Tamai · T. Matsumoto · K. Nagata · K. Otsuka · A. Nakagawa · K. Otsuka · N. Katakami · K. Tomii Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2 Minatojima‑minamimachi, Chuo‑ku, Kobe 650‑0047, Japan e-mail: [email protected]; [email protected] D. Fujimoto e-mail: [email protected]
option for patients with advanced nonsquamous NSCLC with ILD. Keywords Chemotherapy-related exacerbation · Interstitial lung disease · Idiopathic pulmonary fibrosis · Non-small cell lung cancer · Usual interstitial pneumonia · Vascular endothelial growth factor
Introduction Lung cancer is the leading cause of cancer deaths worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 80 % of lung cancers, and the majority are unresectable and metastatic upon initial diagnosis. Cytotoxic platinum-based chemotherapy is the primary therapeutic option for metastatic NSCLC [2]. Evidence indicates that interstitial lung disease (ILD), which is also called diffuse parenchymal lung disease, is associated with lung carcinogenesis [3, 4]. Smokers with interstitial lung abnormalities in unselected populations are relatively common [5, 6]. In addition, the cumulative incidence of lung cancer in patients with idiopathic pulmonary fibrosis (IPF), which is the most common subset of ILD, increased at the rates of 3.3, 15.4, and 54.7 % over 1, 5, and 10 years, respectively [7]. Chemotherapy-related exacerbation of ILD ranges in incidence from 8.7 to 21 %, and it is a fatal complication of treatment of lung cancer [8, 9]. Cytotoxic chemotherapeutics such as gemcitabine and docetaxel induce severe exacerbation of ILD [10, 11]. In contrast, paclitaxel and carboplatin combination chemotherapy is effective and relatively safe for patients with advanced NSCLC with ILD [12, 13]. However, optimal chemotherapy using other agents has not been elucidated.
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1160
Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), which significantly extends overall survival (OS) and progression-free survival (PFS), and it improves the overall response rate (ORR) of patients with advanced nonsquamous NSCLC when combined with paclitaxel and carboplatin [14]. The addition of bevacizumab does not increase the rate of chemotherapy-related pneumonitis; however, BIBF 1120, which inhibits the activities of multiple protein tyrosine kinases such as the VEGF receptor, shows potential for treating patients with IPF [15, 16]. Therefore, we hypothesized that paclitaxel and carboplatin together with bevacizumab may effectively and safely treat patients with advanced nonsquamous NSCLC with ILD. For this purpose, we conducted a retrospective study aimed to evaluate this hypothesis.
Patients and methods Patients We analyzed 21 patients with advanced nonsquamous NSCLC and ILD who received paclitaxel and carboplatin alone (paclitaxel–carboplatin group) or paclitaxel and carboplatin with bevacizumab (paclitaxel–carboplatin– bevacizumab group) at Kobe City Medical Center General Hospital between April 2008 and October 2013. Results were analyzed retrospectively using case and radiographic records. Patients who reported never smoking were designated never smokers, those who smoked within 1 year of the diagnosis were categorized as current smokers, and all others were designated former smokers. The Ethics Committee of Kobe City Medical Center General Hospital approved this study. Treatment Treatment regimens were as follows: (1) Paclitaxel–carboplatin group (PC group): Carboplatin every 4 weeks at a dose determined by the area under the curve (AUC) 4–5 was administered on day 1, and paclitaxel at a dose of 60–70 mg/m2 was administered on days 1, 8, and 15. Each 4-week treatment schedule was designated as one cycle. (2) Paclitaxel–carboplatin–bevacizumab group (PCB group): Carboplatin every 4 weeks at a dose of AUC 4–5 and bevacizumab at a dose of 15 mg/kg were administered on day 1 and paclitaxel at a dose of 70 mg/m2 was administered on days 1, 8, and 15. Each 4-week treatment schedule was designated as one cycle. None of the patients received maintenance chemotherapy or continued therapy beyond the Response Evaluation Criteria in Solid Tumors (RECIST) progression. None of the patients had a contraindication for
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Cancer Chemother Pharmacol (2014) 74:1159–1166
bevacizumab such as having a history of severe pulmonary hemorrhage, pulmonary cavitation, or tumor invasion of major blood vessels. After the PASSPORT study, patients with brain metastasis received the bevacizumab regimen after stereotactic radiotherapy or whole-brain radiotherapy, according to the result of that study [17]. Interstitial lung disease (ILD) Preexisting ILD was diagnosed according to clinical features and pretreatment chest high-resolution computed tomography (HRCT) results. All patients received HRCT according to standard clinical practice, and the presence of ILD was evaluated by at least two pulmonologists. We considered ILD into usual interstitial pneumonia (UIP) and non-UIP patterns. Diagnosis of UIP pattern was determined using CT features, defined by the International Consensus Statement of the American Thoracic Society and the European Respiratory Society, showing subpleural distribution, honeycombing (Fig. 1), traction bronchiectasis, and architectural distortion [18, 19]. Patients with ILD revealed by CT, except for those with the (UIP) pattern, were diagnosed with the non-UIP pattern. Chemotherapy-related exacerbation of ILD was diagnosed according to CT findings (bilateral ground-glass abnormality with or without focal consolidation superimposed on pretreatment interstitial shadow) [20]. We excluded patients with apparent pulmonary infection, pulmonary embolism, or heart failure. Chemotherapyrelated exacerbation of ILD was evaluated according to the presence of pneumonitis/pulmonary infiltrates by the United States National Cancer Institute Common Terminology Criteria version 3.0 as follows: Grade 3: symptomatic, interfering with activities of daily living, and oxygen indicated; Grade 4: life-threatening; and Grade 5: death. To assess the incidence of chemotherapy-related exacerbation of ILD, the duration between the last administration of cytotoxic chemotherapy and the onset of exacerbation of ILD was defined as 4 weeks or fewer. Patient evaluation and statistical analysis A CT scan was performed within 28 days before initiating treatment to assess the primary tumor and was repeated every 2–3 months. All responses were defined according to RECIST. A response was confirmed at least 4 weeks (for a complete or partial response) or 6 weeks (for stable disease) after the first documentation. PFS was measured from the start of treatment to the time of progression. OS was measured from the start of treatment until death by all causes. PFS and OS were determined using the Kaplan– Meier method. The log-rank test was used to compare the cumulative survival of each group. Continuous variables were analyzed using the Student’s t test, and the results
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Fig. 1 HRCT image of the chest. a Subpleural distribution, honeycomb cysts, and bronchiectasis (UIP pattern). b Patchy ground-glass opacity with reticulation, traction bronchiectasis, and bronchovascular bundle thickening (non-UIP pattern)
were expressed as the mean ± standard deviation (SD). Dichotomous variables were analyzed using the Chi-square test or the Fisher’s exact test, as appropriate. The relationship between numerical and categorical variables was compared using the Wilcoxon signed-rank test. All tests were two-tailed, and p
