Abstract
Background: We reported that doxorubicin and cyclophosphamide (DC) followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. However, as one of the side effects of paclitaxel, neuropathy was noted in up to 30% of patients. Cyclooxygenase-2 (COX-2) and its derived prostaglandins play a role in stimulating angiogenesis, inhibiting apoptosis, and suppressing the immune response. Some recent studies showed that COX-2 inhibitors, such as meloxicam, have the potential to enhance tumor suppression and reduce the severity of paclitaxel-induced neuropathy. Patients and Methods: Four cycles of DC (doxorubicin: 60 mg/m2 and cyclophosphamide: 600 mg/m2) administered intravenously (i.v.) on day 1 every 21 days were followed by 12 cycles of paclitaxel i.v. (80 mg/m2) every 7 days, prior to surgery. During paclitaxel therapy, breast cancer patients were administered meloxicam (10 mg per day) daily, when experiencing symptoms of grade 2 neuropathy (motor or sensory). The primary endpoint was the pCR rate achieved with the treatment. Results: Forty-three patients received preoperative chemotherapy between April 2004 and March 2007 at six centers. The patient population was identified from a database of the Japan Breast Cancer Research Network. Clinical responses were rated as clinically complete response (cCR) in 9 patients (22%), clinically partial response (cPR) in 25 patients (59%), and clinically stable disease (cSD) in 9 patients (19%). pCR was seen in 25.6%. In addition, we identified 15 patients, who developed grade 2 neuropathy during paclitaxel therapy and subsequently received meloxicam. Meloxicam application had a marked effect within 28 days of initiation. The sensory neuropathy of the patients was reduced gradually, but their motor neuropathy did not improve. Five out of the 15 patients with neuropathy experienced symptom improvement after meloxicam treatment (p<0.05; before versus after 2 months of meloxicam administration). Furthermore, among the 15 patients, who received meloxicam, clinical responses were rated as cCR in 2 patients, cPR in 4 patients, and cSD in 9 patients. The pCR was seen in 4 patients (26.7%). Conclusion: Although meloxicam in combination with DC and weekly paclitaxel chemotherapy did not show promising therapeutic activity, it may provide some relief for neuropathy.
Breast carcinoma is the most frequent neoplasia in the U.S., Europe, and even in Japan, and it is the most common cause of cancer mortality in this population. Neoadjuvant chemotherapy (NAC) has emerged as a promising step forward in the management of breast cancer. Many studies demonstrated that patients with pathological complete response (pCR) to chemotherapy had a favorable prognosis, while paclitaxel-based chemotherapy is recognized as the best available treatment for breast cancer (1) and the pCR rate is still low (20-30%). Therefore, a new and more effective strategy for the treatment of breast cancer is called for. Recent reports demonstrated cyclooxygenase (COX-2) overexpression in many malignancies including breast cancer (2-5). Pre-clinical studies have shown that selective COX-2 inhibitors lead to some promising results when used with chemotherapy (6, 7). Among several COX-2 inhibitors, meloxicam is often used safely in Japan, but its synergistic effect with chemotherapy has not been reported in breast cancer.
Grading of neuropathy (NCI CTCAE, version 3.0).
Neuropathy is the one of the most frequent side-effects of paclitaxel therapy, and has been reported in up to 30% of patients (8-10). Sensory neuropathy induced by paclitaxel typically presents as numbness and paresthesia with a glove and stocking distribution, with symptoms often appearing within 24 to 72 hours after treatment. These are troublesome to many patients, and may be severe and debilitating in others. Furthermore, several drugs, including nonsteroidal anti-inflammatory agents, corticosteroids, and amifostine (8-10), have been explored as treatments for reducing the neurotoxicity associated with paclitaxel. Recently, COX-2 inhibitors were found to suppress neuropathy and tumor growth (11-14).
Therefore, we performed this study to examine the efficacy and tolerability of a regimen in which preoperative chemotherapy was combined with meloxicam, a selective COX-2 inhibitor.
Patients and Methods
A multicenter study. Forty-three patients received preoperative chemotherapy between April 2004 and March 2007 at six centers. Patients with bilateral, locally advanced, or metastatic disease were excluded. The patient population was identified from a database of the Japan Breast Cancer Research Network.
Treatment plan. Preoperative chemotherapy was described previously (1). In brief, 4 cycles of doxorubicin: 60 mg/m2 and cyclophosphamide: 600 mg/m2 (DC) administered intravenously (i.v.) on day 1 every 21 days were followed by 12 cycles of paclitaxel i.v. (80 mg/m2) every 7 days, prior to surgery. The findings of physical examinations, tumor characteristics, initial dose of paclitaxel, number of treatment cycles, chemotherapy-related toxicities, and symptom severity were recorded every week. In this subset analysis, during paclitaxel therapy, breast cancer patients were administered meloxicam (10 mg per day) daily when they had symptoms of grade 2 or more neuropathy (motor or sensory). Physical examination, tumor characteristics, initial dose of paclitaxel, subsequent dose modifications, number of treatment cycles, chemotherapy-related toxicities, and severity of symptoms were recorded every week. Toxicity was graded using the NCI-CTCAE v.3.0 (Table I). The median time to onset of grade 2 neuropathy was estimated. Furthermore, neuropathy was compared between that before and after meloxicam administration.
Evaluation of efficacy and safety. The disease status was confirmed by physical examination, mammography, and breast ultrasonography and a core or fine-needle biopsy for histopathological diagnosis. During treatment, a white blood cell count was repeated weekly. Biochemistry tests were performed after courses 2 and 4, and cardiac monitoring comprised an Electrocardiogram after course 4 and left ventricular ejection fraction measurement after courses 2 and 4, or after study discontinuation. The tumor response was assessed as a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) in accordance with the standard Response Evaluation Criteria in Solid Tumors (1).
Statistics. The primary endpoint was the pCR rate achieved with the treatment. Secondary endpoints included predictors for pCR, DFS, and safety. A 10-30% pCR rate was reported based on histopathology in preoperative anthracycline plus taxane (PTX) chemotherapy regimens. Analyses were performed with JMP (version 9; SAS Institute Inc., Tokyo, Japan).The significance of differences was determined with the Wilcoxon signed rank test. Differences with probability values less than 0.05 were considered significant.
Results
Patient characteristics. Between April 2004 and March 2007, 43 patients were prospectively enrolled. The characteristics of the study population are presented in Table II. The median age was 50 (range: 20-69) years. The majority of patients had T2 tumors. All the patients were evaluable regarding their response and toxicity. Clinical responses were rated as cCR in 9 patients (22%), cPR in 25 patients (59%), and cSD in 9 patients (19%). Overall, pCR was seen in 25.6%.
Patient characteristics.
In addition, we identified several toxicities (Table III) and 15 patients who developed grade 2 neuropathy during paclitaxel therapy and subsequently received meloxicam. Meloxicam application had a marked effect within 28 days of initiation. The sensory neuropathy of the patients reduced gradually, but their motor neuropathy did not improve (Figure 1). Five out of the 15 patients with neuropathy experienced symptom improvement after meloxicam treatment (p<0.05; before versus after 2 months of meloxicam administration).
Furthermore, among the 15 patients who took meloxicam, clinical responses were rated as cCR in 2 patients, cPR in 4 patients, and cSD in 9 patients. The pCR was seen in 4 patients (26.7 %). In addition, multiple logistic regression analysis was performed to examine factors including menopausal status, tumor size, ER status, PgR status, HER2 status, and clinical response (Table IV). The estimated 4-year DFS was 78% for all patients. However, in the present study, there was no additional effect of meloxicam on chemotherapy in terms of the pCR rate, response rate, and DFS.
Treatment-related toxicities.
Discussion
In breast cancer, a number of studies have explored the relationship between COX-2 expression and the clinical outcome (2-5). COX-2 inhibitors play an important role in the pathogenesis of breast cancer (15-17). To our knowledge, this is the first study to investigate the efficacy of a COX2 inhibitor in breast cancer.
In this study, we examined the efficacy and toxicity of a COX-2 inhibitor (meloxicam) in combination with chemotherapy for breast cancer patients. Indeed, several in vitro and in vivo studies showed the effect of COX-2 inhibition in enhancing the tumor response to chemotherapeutic agents (6, 7). Furthermore, an enhanced response was shown when a COX-2 inhibitor was combined with paclitaxel in clinical setting (11-14). However, in the present study, there was no additional effect of meloxicam on chemotherapy in terms of the pCR rate, response rate, and DFS (data not shown).
On the contrary, paclitaxel is well-known to induce neurotoxic effects, some of which are peripherally sensory in nature, while others are symptoms of motor neuropathy. In such patients, their sensory neuropathy was reduced by the addition of meloxicam, but their motor neuropathy was not improved. A previous study showed that meloxicam reduced the severity of paclitaxel-induced neuropathy in lung cancer patients and that grade 2 peripheral neuropathy occurred in only one patient among the 25 patients after the repeated administration of paclitaxel and carboplatin (11). In accordance with the findings of this previous study, meloxicam-containing preparations appear to offer some benefit as an adjunctive treatment for paclitaxel-induced neuropathy.
The mechanism of paclitaxel-induced neuropathy is unclear. In patients receiving paclitaxel, the neuropathy induced is dose-dependent (1). However, in fact, the addition of meloxicam reduced neuropathy, and so it is important that patients receive appropriate education and follow-up while receiving meloxicam because early recognition may be the key to the management of neuropathy.
Title for figure Sensory neuropathy began to disappear after 1 month of meloxicam treatment (1M). Five out of the 15 patients with neuropathy experienced symptom improvement after meloxicam treatment (p<0.05; before versus after 2 months of meloxicam administration, 2M 1.1±0.2). However, motor neuropathy of the patients did not improve.
Prediction of pCR (G3) by logistic regression.
There are still many questions to be answered as to the potential optimal use of COX-2 inhibition in breast cancer therapy. When our trial began, selective COX-2 inhibitors were thought to be much better tolerated than nonselective nonsteroidal anti-inflammatory drugs because of their lower rates of associated gastrointestinal toxicity. Despite the now known association of thrombotic events with their chronic use, if COX-2 inhibitors were found to markedly add to tumor control, it would be reasonable to assume an increased risk of myocardial infarction (18). In our study, there was no such serious adverse events. Evaluation of the effect of COX-2 inhibitors on chemotherapy should be undertaken in a randomized study.
- Received June 16, 2011.
- Revision received July 19, 2011.
- Accepted July 20, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.