Introduction
As systemic chemotherapy has had disappointing results in patients with hepatocellular carcinoma (HCC) [
1‐
5], HCC has generally been considered to be chemoresistant. Sorafenib, a multi-kinase inhibitor that blocks tumor growth and cell proliferation, was the first systemic chemotherapeutic agent found to improve the survival time of patients with advanced HCC in the SHARP trial and Asian Pacific trials [
1,
2,
6]. Sorafenib is therefore a novel treatment for patients with advanced HCC. However, it is associated with a low tumor response rate, minimal survival advantage, and high rate of adverse events [
1‐
4].
The reported significant adverse events caused by sorafenib include diarrhea, skin rash (including hand-foot skin reactions), fatigue, liver dysfunction, and hypertension [
1‐
4]. However, there have been few reported cases of interstitial lung disease such as acute interstitial pneumonia (AIP) [
7,
8]. Safety information for sorafenib therapy in patients with renal cell carcinoma (RCC) was presented in Japan in December 2008, and reported four cases of acute respiratory failure among 2,000 patients with RCC who had been treated with sorafenib [
9]. The clinical features, risk factors, and prognostic factors of sorafenib-induced AIP are not well known at present [
7,
8]. As AIP is a life-threatening condition, a better understanding of sorafenib-induced AIP is required. We report three cases of AIP during sorafenib therapy in patients with advanced HCC.
Discussion
Commonly reported adverse events caused by sorafenib include diarrhea, skin rash (including hand-foot skin reactions), fatigue, liver dysfunction, and hypertension. However, there have been few reported cases of sorafenib-induced interstitial lung disease [
1,
2,
4,
7,
8].
From June 2009 to February 2012, we treated 105 patients with advanced HCC with sorafenib. Six of these patients (5.8 %) developed pulmonary disorders during sorafenib therapy, of which three (2.9 %) were diagnosed with probable sorafenib-induced AIP. The other three patients (2.9 %) with pulmonary disorders had acute bacterial pneumonia and/or carcinomatous lymphangitis. This was a higher incidence of AIP than reported in the all-patient post-marketing surveillance in Japan [
10]. The reasons for this high incidence may include the high proportions of smokers and patients with pretreatment respiratory dysfunction in our treatment group.
Patients with advanced HCC are generally immunodeficient, making them susceptible to pneumonia [
5]. Carcinomatous lymphangitis should also be considered in patients with malignancy who develop respiratory disorders. In the present three cases, dyspnea was associated with increased serum KL-6 or SP-D concentrations, and the results of blood and sputum examinations suggested that major infection was unlikely. Chest CT showed typical patterns of extensive bilateral interstitial lung disease in all patients, which was distinguishable from carcinomatous lymphangitis [
11]. We therefore diagnosed probable sorafenib-induced AIP, although other conditions could not be completely excluded.
Case 1 had a positive DLST, suggesting an allergic reaction to sorafenib. Early discontinuation of sorafenib and administration of PSL resulted in rapid improvement of his respiratory function, supporting allergy as the cause of his AIP. In case 2, we made a definitive diagnosis of AIP by bronchoscopy. The absence of pus in his bronchi, and increased LDH and lymphocytes in his BAL fluid with no evidence of pathogens, helped us to rule out major infections and diagnose AIP. In case 3, it was difficult to conclusively rule out an infectious cause. However, the findings in this case were strongly suggestive of sorafenib-induced AIP.
The characteristics of, and risk factors for, sorafenib-induced AIP are not well known. Our three cases were all men aged over 75 years, and were all smokers (Brinkman index approximately 1,400 in case 1, 400 in case 2, and 800 in case 3). In addition, pretreatment respiratory function testing did not show restrictive lung disease in any of the cases (percent predicted vital capacity 47 % in case 1, 76 % in case 2, and 58 % in case 3). However, pretreatment chest CT did not show evidence of interstitial lung disease, and none of the patients had respiratory symptoms.
Several studies have reported the risk factors for gefitinib-induced AIP in patients with unresectable lung cancer [
12,
13]. According to the West Japan Thoracic Oncology Group report on 1,661 patients with lung cancer who were treated with gefitinib, AIP is associated with male sex (odds ratio [OR]: 3.9), smoking (OR: 4.51), and a past history of interstitial pneumonia or respiratory disease (OR: 2.83) [
13]. We observed almost the same factors in our three cases.
Table
1 shows the reported cases of sorafenib-induced AIP to date. Although results of pretreatment respiratory function testing were not reported in previous cases, one previous case had a history of interstitial lung disease. The time from initiation of sorafenib therapy to onset of respiratory failure varied from 5 days to 1 year. In all cases, chest X-ray or CT showed GGOs. Our case 2 is the first case in which bronchoscopy was performed. Five of the six cases received steroid therapy.
Table 1
Summary of the reported cases of sorafenib-induced AIP, including our cases
Our case 1 | 2012 | 76 | Male | DM and OMI/DM | None | 1400 | Social drinker | HCV | HCC | IVA | A | TACE, RFA | 47 | 90 | 5 days | mPSL 20 mg/day | Recovered |
Our case 2 | 2012 | 75 | Male | Pneumothorax/None | None | 400 | Social drinker | HCV | HCC | II | A | OP, TACE, RFA | 76 | 75 | 11 days | Hydrocortisone 1 g/day | Died |
Our case 3 | 2012 | 77 | Male | HT and PH/None | None | 800 | None | HCV | HCC | IVB | A | OP, TACE, RAD | 58 | 80 | 41 days | Hydrocortisone 1 g/day | Died |
Myung et al. | 2010 | 74 | Male | None/NS | None | 100 | NS | HCV | HCC | IVA | A | TACE, RFA RAD | NS | NS | 24 days | mPSL 30 mg/day | Recovered |
Ide et al. | 2010 | 55 | Male | None/NS | None | “smoker” | NS | NS | RCC | IV | NS | IL2 | NS | NS | 1 year | Dexamethasone 4 mg/day | Died |
Bayera
| 2008 | 70 | Male | RA and UIP/NS | NS | NS | NS | NS | RCC | IV | NS | None | NS | NS | 40 days | None | Died |
Drug-induced pneumonia is usually diagnosed by physical examination and X-ray and CT findings. Typical early symptoms of AIP are cough, fever, and dyspnea. Fine crackles can be heard on chest auscultation. However, drug-induced lung disease cannot be definitively diagnosed by physical, laboratory, and imaging findings. Chest X-rays at presentation are likely to miss or underestimate lung disease, but chest CT may be more useful. It is recommended that steroid therapy should be started as soon as possible [
14]. In case 1, we diagnosed AIP by CT on the first day of respiratory symptoms and started steroid therapy immediately, whereas in cases 2 and 3 steroid therapy was started a few days after the onset of respiratory symptoms. In the reported fatal case of sorafenib-induced AIP in a patient with RCC, steroid therapy was started 12 days after discontinuing sorafenib. These cases indicate the importance of early diagnosis and immediate initiation of steroid therapy in patients with sorafenib-induced AIP.
The mechanisms of sorafenib-induced interstitial lung disease remain unclear. In general, drug-induced lung disease may be immune-mediated or may result from direct toxicity [
15]. The present cases may reflect these two mechanisms. Case 1 had a positive DLST and case 2 had a high serum level of IgE, suggesting an immune-mediated mechanism or acute allergic reaction. Case 3 may have resulted from direct toxicity.
Recently, Myung et al. [
7] suggested that sorafenib-induced pulmonary toxicity might be related to its ability to inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Several studies have reported on the relationship between regulation of VEGF and AIP [
16‐
19]. VEGF plays a role in the maintenance of structure and function of alveolar (and other) capillaries. A decrease in the amount or activity of VEGF leads to apoptosis of bronchoalveolar cells, resulting in remodeling of the pulmonary architecture and honeycomb changes in lung structure. Many studies have reported a reduction in the amount of intrapulmonary VEGF in the early stages of lung injury, and normalization of intrapulmonary VEGF after recovery in patients with acute respiratory distress syndrome [
16‐
19].
Sorafenib treatment, which suppresses VEGF, might induce remodeling of bronchoalveolar structures resulting in AIP. Although there are several hypotheses regarding the mechanisms of sorafenib-induced AIP, the pathways remain unclear [
7,
8]. Further studies of the molecular mechanisms responsible for sorafenib-induced lung injury are required, and methods of preventing and managing such injury need further investigation.