Introduction
Interstitial lung diseases (ILDs) with lung cancer
(ILD-LC) have been reported in 9.8–38% of ILD patients (1). There is no standard treatment for
ILD-LC, regardless of whether small cell lung cancer (SCLC) or
non-small cell lung cancer (NSCLC) is diagnosed. Surgical resection
and anticancer agents are associated with a high risk of ILD
exacerbation (2). In patients with
advanced ILD-NSCLC, carboplatin plus paclitaxel (CP) therapy is a
common treatment option. However, a prospective study showed that
5.6% of patients experience acute exacerbation of ILD-NSCLC with CP
therapy (3).
Findings of a clinical trial showed that the
addition of bevacizumab to CP (CP-B) improved the overall survival
in patients with advanced non-squamous cell NSCLC (4). This drug regimen is therefore
considered a standard treatment option for this patient population.
However, the safety of CP-B in patients with ILD-NSCLC remains to
be clarified, especially with respect to lung toxicity. In the
present study, the safety and efficacy of CP-B therapy in ILD-NSCLC
patients were retrospectively investigated.
Patients and methods
Patients
ILD-NSCLC patients who newly received CP-B therapy
between January, 2010 and December, 2011 at the Osaka Prefectural
Medical Center for Respiratory and Allergic Diseases were
retrospectively investigated based on their medical records. This
study was approved by the Institutional Review Board. Five patients
initially received CP-B therapy between January, 2010 and December,
2011. The four patients (male; age range 69–70 years) who completed
the CP-B treatment were included in this study. Three of the four
patients were smokers. These patients did not have brain
metastases, a history of hemoptysis or an easy to bleed tumor at
the initiation of the CP-B treatment.
Methods
ILD was identified by conventional or
high-resolution computed tomography (CT) images obtained prior to
chemotherapy. Where CT images showed bilateral honeycomb, reticular
or grand-glass opacities superior in the subpleural areas of both
lungs, ILD was confirmed. Usual interstitial pneumonia (UIP)
patterns were defined based on the presence of traction
bronchiectasis and subpleural honeycombing. No bronchoalveolar
lavage or lung biopsy were performed to confirm interstitial
pneumonia. In addition, patients with a history of exposure to
dust, such as asbestos, and those with collagen diseases were not
excluded. Response Evaluation Criteria in solid tumors (5) were used for the evaluation of
treatment response. Adverse events were evaluated using the Common
Terminology Criteria for Adverse Events version 4.0. The time
period to treatment failure was measured as the period between
diagnosis and treatment cessation, as indicated by the physician,
or disease progression.
Results
Five patients received CP-B therapy between January,
2010 and December, 2011. The 4 patients who completed the CP-B
treatment were included in this study. The patients were males, had
histologically confirmed adenocarcinomas and were smokers. The CT
pattern of the ILD cases was ‘non-UIP’ (Table I). None of the patients had ever
received any treatment for pneumonitis, such as steroids or
anti-fibrotic agents. CP-B was administered for 1–6 cycles. The
dose of carboplatin was the area under the curve 5, paclitaxel was
200 mg/m2 and bevacizumab was 15 mg/kg at treatment
initiation. The attending physician modified these doses according
to toxicity. Three of the 4 patients received maintenance
bevacizumab therapy (Table II).
Only 1 patient showed a partial response. Neutropenia was the most
frequent adverse event. One patient experienced gut perforation
(grade 4) during the first cycle of CP-B and underwent surgery.
Thereafter, CP alone was administered to this patient. No pulmonary
toxicity was observed when comparing pre- and post-treatment lung
parenchyma CT findings. Treatment was terminated due to disease
progression in all the patients, with the exception of 1 patient.
The time period to treatment failure was 25–427 days.
 | Table IPatient characteristics. |
Table I
Patient characteristics.
| Case | Age (years) | P-Y | His | ILD pattern | PS | Cyc | Main | Res | Reason | TTF (days) |
|---|
| 1 | 69 | 76.5 | Ad | Non-UIP | 2 | 1 | - | NE | Toxicity | 25 |
| 2 | 69 | 17 | Ad | Non-UIP | 1 | 6 | 6 | PR | PD | 281 |
| 3 | 71 | 37 | Ad | Non-UIP | 0 | 4 | 3 | SD | PD | 200 |
| 4 | 70 | 50 | Ad | Non-UIP | 1 | 4 | 10 | SD | PD | 487 |
| Table IITreatment-related toxicity. |
Table II
Treatment-related toxicity.
| Case | Neu | Hgb | Plt | U-prot | HpT | Others |
|---|
| 1 | - | - | - | - | - | G4 gut
perforation |
| 2 | G4 | - | - | G2 | - | |
| 3 | G4 | G2 | G2 | - | - | G2 infection |
| 4 | G3 | G2 | - | - | G2 | |
Total number of ILD-NSCLC patients
administered CP-B
A total of 162 patients (35 with SCLC and 127 with
NSCLC) were diagnosed with ILD-LC between January, 2010 and
December, 2011 in our Institute. A total of 24 patients with NSCLC
were administered anticancer agents, whereas 15 patients (including
the 4 patients assessed in the present study) received CP. The
Japanese Ministry of Health, Labor and Welfare approved the use of
bevacizumab for lung cancer in November 2009. The use of
bevacizumab was examined at the end of 2009. Patients without
metastatic brain tumors or evidence of thrombosis, hemoptysis or
cavity lesions [5 of 9 CP patients (55.6%)] were defined as
eligible to receive bevacizumab treatment. The remaining patients
were defined as ineligible to receive bevacizumab due to brain
metastasis, cavity formation, an easy to bleed tumor or fresh
cranial infarction. After 2010, 5 of the remaining 6 CP patients
were administered bevacizumab. The rate of bevacizumab use in
non-squamous cell NSCLC patients receiving chemotherapy was
41.7%.
Discussion
Findings of this study have shown that CP-B therapy
in ILD-NSCLC patients was not associated with pulmonary toxicity.
However, the population in this study appeared to be at a low risk
due to the adverse events observed.
The rate of bevacizumab-related pneumonitis has been
reported to be 0.19% in a post-marketing investigation (6). This study did not identify the
difference between the effect of bevacizumab compared with that of
other agents used in combination with bevacizumab.
Bevacizumab-related pneumonia has not yet been reported in lung
cancer patients. In colorectal cancer, ILD was found to occur in
3.84% of patients receiving standard chemotherapy with bevacizumab
(7). The ILD patients included in
this study were males, 3 of 4 patients were smokers, while 1
patient was diagnosed with pulmonary fibrosis. An additional study
reported the case of bevacizumab-related ILD in a 64-year-old woman
(8).
In this study, one patient experienced a severe
adverse event (grade 4 gut perforation). More than half of the
toxic deaths were found to occur within two treatment cycles in two
previously published clinical trials (4,9).
These results indicate that ILD-NSCLC patients receiving CP-B
treatment should be hospitalized for a minimum of two treatment
cycles. Maintenance treatment with bevacizumab was safe for at
least 3 cycles. Therefore, this regimen is considered suitable for
the selected ILD-NSCLC patients.
New molecular-targeted drugs are potential future
treat ment options. BIBF1120 is a multiple-target tyrosine kinase
inhibitor that targets vascular endothelial (VEGF),
platelet-derived growth factors (PDGF), and fibroblast growth
factor receptor (FGFR). Compared with placebo in IPF patients,
high-dose BIBF1120 was found to inhibit the decrease in lung
function and was associated with fewer acute exacerbations
(10). A clinical trial comparing
250 and 150 mg BIBF1120 twice daily in NSCLC patients unresponsive
to platinum drugs did not show a difference in PFS (11). However, a study assessing the
combination of docetaxel (12) or
pemetrexed (13) and BIBF1120 is
currently being conducted. Depending on the results of this trial,
BIBF1120 may be a key agent for the treatment of advanced
ILD-NSCLC.
The present study was limited in size, comprising
only four patients, for whom data were collected retrospectively.
Additionally, no detailed ILD background was available and UIP as
well as non-UIP patterns were evaluated using only CT.
CP-B treatment in patients with ILD-NSCLC did not
induce pulmonary toxicity. Although this population appears to be
at a low risk, this regimen was identified as an alternative
treatment option in such patients. Novel molecular-targeting agents
may alter the treatment of ILD-LC patients.
References
|
1.
|
Bouros D, Hatzakis K, Labrakis H and
Zeibecoglou K: Association of malignancy with diseases causing
interstitial pulmonary changes. Chest. 121:1278–1289. 2002.
View Article : Google Scholar : PubMed/NCBI
|
|
2.
|
Isobe K, Hata Y, Sakamoto S, Takai Y,
Shibuya K and Homma S: Clinical characteristics of acute
respiratory deterioration in pulmonary fibrosis associated with
lung cancer following anticancer therapy. Respirology. 15:88–92.
2010. View Article : Google Scholar
|
|
3.
|
Minegishi Y, Sudoh J, Kuribayasi H,
Mizutani H, Seike M, Azuma A, Yoshimura A, Kudoh S and Gemma A: The
safety and efficacy of weekly paclitaxel in combination with
carboplatin for advanced non-small cell lung cancer with idiopathic
interstitial pneumonias. Lung Cancer. 71:70–74. 2011. View Article : Google Scholar : PubMed/NCBI
|
|
4.
|
Sandler A, Gray R, Perry MC, Brahmer J,
Schiller JH, Dowlati A, Lilenbaum R and Johnson DH:
Paclitaxel-carboplatin alone or with bevacizumab for non-small cell
lung cancer. N Engl J Med. 355:2542–2550. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
5.
|
Therasse P, Arbuck SG, Eisenhauer EA,
Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van
Oosterom AT, Christian MC and Gwyther SG: New guidelines to
evaluate the response to treatment in solid tumors European
Organization for Research and Treatment of Cancer, National Cancer
Institute of the United States, National Cancer Institute of
Canada. J Natl Cancer Inst. 92:205–216. 2000. View Article : Google Scholar
|
|
6.
|
Chugai Pharmaceutical Co, Ltd.: http://chugai-pharm.jp/hc/ss/pr/safe/report/ava/index.html.
Accessed July 26, 2012.
|
|
7.
|
Usui K, Katou Y, Furushima K, Tanaka Y,
Tanai C and Ishihara T: Interstitial lung disease during
chemotherapy combined with oxaliplatin and/or bevacizumab in
advanced colorectal cancer patients. Jpn J Clin Oncol. 41:498–502.
2011. View Article : Google Scholar : PubMed/NCBI
|
|
8.
|
Tamura J, Nakauchi M, Nakayama Y,
Kitaguchi K, Sakikubo M, Ura K, Taira K, Ohe H, Yoshikawa A,
Ishigami S and Baba N: A case of interstitial pneumonitis induced
by FOLFIRI+bevacizumab combination therapy for liver and lung
metastasis of colon cancer. Gan To Kagaku Ryoho. 36:2665–2668.
2009.(In Japanese).
|
|
9.
|
Niho S, Kunitoh H, Nokihara H, Horai T,
Ichinose Y, Hida T, Yamamoto N, Kawahara M, Shinkai T, Nakagawa K,
Matsui K, Negoro S, Yokoyama A, Kudoh S, Kiura K, Mori K, Okamoto
H, Sakai H, Takeda K, Yokota S, Saijo N and Fukuoka M; JO19907
Study Group: Randomized phase II study of first-line
carboplatin-paclitaxel with or without bevacizumab in Japanese
patients with advanced non-squamous non-small cell lung cancer.
Lung Cancer. 76:362–367. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
10.
|
Richeldi L, Costabel U, Selman M, Kim DS,
Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G,
Brun M, Gupta A, Juhel N, Kluglich M and du Bois RM: Efficacy of a
tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl
J Med. 365:1079–1087. 2011. View Article : Google Scholar : PubMed/NCBI
|
|
11.
|
Reck M, Kaiser R, Eschbach C, Stefanic M,
Love J, Gatzemeier U, Stopfer P and von Pawel J: A phase II
double-blind study to investigate efficacy and safety of two doses
of the triple angiokinase inhibitor BIBF 1120 in patients with
relapsed advanced non-small cell lung cancer. Ann Oncol.
22:1374–1381. 2011. View Article : Google Scholar : PubMed/NCBI
|
|
12.
|
US National Institutes of Health:
Lume-Lung 1: BIBF 1120 plus docetaxel as compared to placebo plus
docetaxel in 2nd line non-small cell lung cancer. http://clinicaltrials.gov/ct2/show/NCT00805194.
Accessed July 26, 2012.
|
|
13.
|
US National Institutes of Health:
Lume-Lung 2: BIBF 1120 plus pemetrexed compared to placebo plus
pemetrexed in 2nd line nonsquamous NSCLC. http://clinicaltrials.gov/ct2/show/NCT00806819.
Accessed July 26, 2012.
|
