Date Published: June 7, 2018
Publisher: Public Library of Science
Author(s): Nobuyuki Koyama, Sou Katayanagi, Shigeyuki Kawachi, Amarjit Mishra.
Combination treatment with ramucirumab and paclitaxel shows significant efficacy in patients with advanced gastric cancer as a second-line standard therapy. However, limited information is available about the development of pneumonitis associated with this treatment in clinical practice. This study aimed to characterize this form of pneumonitis and identify the risk factors for its onset.
We retrospectively analyzed the medical records of 44 patients with gastric cancer who received combination treatment with ramucirumab and paclitaxel from 2016 to 2017. Then, the clinicopathological characteristics of patients who developed treatment-related pneumonitis were evaluated and further compared with those of patients who did not.
Six patients (13.6%) developed pneumonitis within five treatment cycles, and in five cases, remission was observed after cessation of combination treatment alone. The onset of pneumonitis was independently associated with pre-existing interstitial lung disease (ILD) (p = 0.025; odds ratio = 206.4). Patients with pneumonitis showed reduced time to treatment failure (median 56 vs. 138 days; p = 0.008), as compared with those without pneumonitis. Most patients with pre-existing ILD with a usual interstitial pneumonia (UIP) pattern developed pneumonitis.
In clinical practice, pneumonitis associated with the combination treatment of ramucirumab and paclitaxel was generally mild, but common. Patients with gastric cancer with pre-existing ILD, particularly those presenting with a UIP pattern, undergoing this combination treatment, should be carefully monitored for the development of treatment-related pneumonitis.
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer death worldwide, despite recent advances in multimodal therapy . In pharmacotherapeutic strategies, combination chemotherapy with platinum plus fluoropyrimidine is the first-line standard therapy for advanced GC [2–4]. A second-line therapy, involving combination treatment with ramucirumab (RAM), an anti-vascular endothelial growth factor receptor-2 (VEGFR-2) monoclonal antibody, and solvent-paclitaxel (PTX), also improves overall survival (OS) , on the basis of the beneficial outcomes of a global phase III trial and is currently commonly employed as the second-line regimen for patients with GC .
In the present study, pneumonitis associated with RAM and PTX combination treatment occurred more commonly than reported in a previous clinical trial . In these patients, the onset of pneumonitis was independently associated with pre-existing ILD. Patients with pre-existing ILD were older than those without pre-existing ILD in univariate analysis (data not shown). Although patients who developed pneumonitis were also older than those who did not in univariate analysis, multivariate logistic regression analysis showed no association between age and the onset of pneumonitis. Although no information on pre-existing ILD was provided in that trial report , a previous retrospective study of patients with NSCLC with pre-existing ILD showed a high incidence of pneumonitis associated with PTX monotherapy (21.4%) . These results indicate that pre-existing ILD is potently associated with the onset of pneumonitis. On the other hand, in this study, Kaplan–Meier survival curves and log-rank tests showed that pre-existing ILD is also associated with TTF and OS, along with the onset of pneumonitis. However, a Cox proportional hazard model showed no independent associations between pre-existing ILD and TTF or OS. Thus, both pre-existing ILD and the onset of pneumonitis are significantly associated with TTF and OS individually, whereas the onset of pneumonitis may be more directly associated with TTF and OS than pre-existing ILD. The findings of the present study suggest that pre-existing ILD may be a risk factor for the onset of pneumonitis associated with RAM and PTX combination treatment in patients with GC. Furthermore, pre-existing ILD and the onset of pneumonitis may be predictive factor for TTF and OS individually. In particular, the onset of pneumonitis was independently associated with TTF, but not with OS. Most pneumonitis events were mild and in fact, more than half of patients who developed pneumonitis underwent subsequent chemotherapies; hence, the onset of pneumonitis may cause the cessation of the combination treatment but may not be an independent prognostic factor for OS.
The present study identified the presence of pre-existing ILD as a risk factor for pneumonitis associated with RAM and PTX combination treatment, a second-line standard pharmacotherapy in patients with GC. Furthermore, a UIP pattern of pre-existing ILD may have an impact on the onset of this treatment-related pneumonitis. Patients with GC with pre-existing ILD, particularly those presenting with a UIP pattern, undergoing combination treatment with RAM and PTX, should be carefully monitored for the development of treatment-related pneumonitis.