Loxoprofen Sodium and Survival in Older People with Advanced Non–Small Cell Lung Cancer

To the Editor: Non–small cell lung cancer (NSCLC) is common in older people, and most of them are diagnosed with advanced disease. The use of systemic chemotherapy in these patients has not been established because of its uncertain effectiveness.1 Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used in older people with pain caused by various diseases. We recently reported that loxoprofen sodium (LOX), one of the most prescribed NSAIDs in Japan, had anticancer effects in vitro and in animals by inhibiting angiogenesis via modulating vascular endothelial growth factor.2 To investigate whether LOX improves survival in older patients with advanced NSCLC, we conducted a retrospective review. We reviewed all 240 consecutive patients aged 65 and older with Stage IIIB3 or IV NSCLC seen at the Geriatric and Respiratory Department of Tohoku University Hospital between January 1998 and January 2002. Pretreatment investigation for all patients included age, symptoms and signs at presentation, weight loss in the previous 6 months, comorbid disease, extent of tumor, and determination of Eastern Cooperative Oncology Group performance status (PS). We defined LOX users as subjects who were regularly prescribed LOX as long as they could orally take medicine. Thoracic radiotherapy or chemotherapy was planned according to the pretreatment investigation by three well-trained pulmonary oncologists. Written informed consent was obtained from each subject. Thoracic radiotherapy, total dose of which ranged from 50 gray (1 gray=1 J/kg) to 60 gray, was performed using a linear accelerator for each patient who had locally advanced NSCLC. The 144 patients receiving chemotherapy were treated with 25 mg/m2 vinorelbine and 80 mg/m2 cisplatin or 60 mg/m2 docetaxel and 80 mg/m2 cisplatin every 3 weeks. Survival was calculated from the diagnosis to the date of death or last follow-up. Multivariate Cox regression analysis was performed to assess the effect of prognostic factors (specifically, age, sex, stage, brain metastasis, comorbid disease, PS, weight loss, thoracic radiotherapy, chemotherapy, regular use of LOX, and cancer-related pain) on survival. Of 240 patients reviewed, 17 who regularly took NSAIDs other than LOX and six who discontinued LOX (three gastric ulcer, two renal insufficiencies, and one edema) were excluded, leaving 217 patients (mean age±standard deviation=73±6) to be analyzed in this study. Their characteristics are displayed in Table 1. Multivariate Cox regression analysis showed that PS-1, PS-2, PS-3, and PS-4 were negative prognostic factors in terms of survival compared with PS-0. Weight loss of more than 5% in the previous 6 months and Stage IV were negative prognostic factors. Brain metastasis was a negative prognostic factor (relative risk (RR)=2.87, 95% confidence interval (CI)=1.72–4.80). Thoracic radiotherapy was a positive prognostic factor. Comorbid disease, chemotherapy, and cancer-related pain had no significant effect on survival. After adjustment for these prognostic factors, the RR of LOX users was 0.63 (95% CI=0.47–0.86, P=.03) for death. Median survival was 284 days in the LOX users and 213 days in the nonusers. The mean dose of LOX was 142±52 mg/d. Of 88 regular LOX-users, 52 (59%) took LOX for cancer-related pain and 31 for chronic pain for arthritis or headache. No serious adverse effects of LOX were observed. Forty nonusers had cancer-related pain; they were treated with morphine. Nonusers were 72 patients with adenocarcinoma, 54 with squamous cell carcinoma, and three with large-cell carcinoma; users were 44 patients with adenocarcinoma, 39 with squamous cell carcinoma, and five with large-cell carcinoma. There was no significant difference in response rate to chemotherapy between users and nonusers of LOX (0 complete response,4 9 partial response, and 49 stable or progressive diseases in the LOX users; 0 complete response, 19 partial response, and 67 stable or progressive diseases in the nonusers). There were neutropenia (6 users, 8 nonusers), renal failure classified as Grade 3 toxicity (2 each),5 and pneumonia classified as Grade 4 (2 users, 4 nonusers) in the course of chemotherapy. There were three chemotherapy-related deaths (1 user, 2 nonusers). These data support the hypothesis that regular use of LOX may prolong survival in advanced NSCLC. This is the first study of NSAIDs targeting patients with advanced NSCLC, but is limited by its dependence on a retrospective study. At present, the administration of NSAIDs should be regarded as therapy for pain but may represent a useful adjunctive treatment in the management of advanced NSCLC, especially for older people.

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