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Journal of Cancer Research and Therapeutics, Vol. 7, No. 4, October-December, 2011, pp. 442-447 Original Article Efficacy and safety of concurrent chemoradiation with weekly cisplatin ± low-dose celecoxib in locally advanced undifferentiated nasopharyngeal carcinoma: A phase II-III clinical trial Mohammad Mohammadianpanah1, Sasan Razmjou-Ghalaei2, Amin Shafizad3, Yaghoub Ashouri-Taziani1, Bijan Khademi4, Niloofar Ahmadloo1, Mansour Ansari1, Shapour Omidvari1, Ahmad Mosalaei5, Mohammad Amin Mosleh-Shirazi1 1 Department of Radiation Oncology, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran Code Number: cr11118 DOI: 10.4103/0973-1482.92013 Abstract Background: This is the first study that aimed to determine the efficacy and safety of concurrent chemoradiation with weekly cisplatin ± celecoxib 100 mg twice daily in locally advanced undifferentiated nasopharyngeal carcinoma. Keywords: Celecoxib, chemotherapy, concurrent chemoradiation, cyclooxygenase-2 (COX-2) inhibitors, locally advanced undifferentiated nasopharyngeal carcinoma, weekly cisplatin Introduction Nasopharyngeal carcinoma has unique features of epidemiology, staging, and treatment compared to other cancers of the head and neck. The majority of patients with nasopharyngeal carcinoma present at locally advanced stage. Radiation therapy (RT) alone or combined chemoradiation is the current cornerstone in the management of nasopharyngeal carcinoma. [1],[2] The poor prognosis of locally advanced disease has led to increasing interests in exploring the use of novel antineoplastic agents in these patients. Cyclooxygenase-2 (COX-2) is one interesting potential target for the treatment of nasopharyngeal carcinoma. COX-2 enzyme overexpresses in many malignant tumors, as well as nasopharyngeal carcinoma and is associated with more aggressive tumor behavior and poor prognosis. Several preclinical studies on selective COX-2 inhibitors, such as celecoxib, have shown that these agents have antitumor, antiangiogenesis, and radiosensitizing effects. [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] In addition, there are evidences that COX-2 inhibitors have been associated with significant reduction in vascular permeability and decrease in acute and chronic inflammation. [15] Celecoxib has been progressively used in clinical studies for improving the response to therapy in many cancers. [16],[17],[18],[19],[20] This is the first study that aimed to determine the efficacy and safety of concurrent chemoradiation with weekly cisplatin ± celecoxib 100 mg twice daily in locally advanced undifferentiated nasopharyngeal carcinoma. Materials and Methods This phase II-III study enrolled patients with newly diagnosed locally advanced (T3-T4 and/or N2-N3, M0) undifferentiated nasopharyngeal carcinoma. From January 2007 to November 2008, 53 patients with locally advanced undifferentiated nasopharyngeal carcinoma were randomly assigned to concurrent chemoradiation with weekly cisplatin (30 mg/m 2 ) plus either celecoxib 100 mg twice daily (study group, n = 26) or placebo (control group, n = 27). The trial was approved by the local university ethics committee in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All the patients provided written informed consent prior to their inclusion in the study. The diagnosis of the disease was based on nasopharyngeal biopsy and a histopathologic examination of the specimen. Eligible patients had to be aged 15-80 years, Karnofsky performance score of ≥70 and have biopsy-proven, newly diagnosed locally advanced undifferentiated nasopharyngeal carcinoma and with normal or acceptable kidney, liver, cardiovascular, and bone marrow functions. Exclusion criteria included prior treatment for nasopharyngeal carcinoma, clinical and imaging evidence of distant metastasis before or during the trial, inability to receive celecoxib or chemotherapy for any reason, presence of severe cardiovascular, kidney, liver, inflammatory bowel disease, or coagulation disorders, and patients' refusal to participate in the trial or to sign on the consent form. All the patients were initially treated with concurrent chemoradiation with weekly cisplatin (30 mg/m 2 ) from the first day of RT, up to 7 cycles. They received a total dose of 70 Gy with 2 Gy daily fractions in 7 weeks with conventional external beam RT using megavoltage telecobalt units or linear accelerator photons. The primary site and upper cervical lymph nodes were treated with two lateral parallel opposed fields; the lower cervical lymph nodes were treated with a separate en face anterior field with a central block. The spinal cord was excluded from the radiation fields after 44 Gy. After 50 Gy, RT was continued to the primary tumor, using reduced size fields, up to 70 Gy. The dose was calculated at the central axis of the upper field. Metastatic cervical lymph nodes were boosted through a direct electron field or anterior and posterior neck fields with a central block and a dose of 15-20 Gy. Three patients were excluded due to early skeletal metastasis (2 patients) or chemotherapy refusal (1 patient), during the course of concurrent chemoradiation. After completion of concurrent chemoradiation, all the patients received adjuvant chemotherapy in an outpatient setting, consisting of cisplatin 70 mg/m 2 for day 1, and 5-fluorouracil (5-FU) 750 mg/m 2 /day with 8-h infusion on days 1-3, which was repeated every 3 weeks, up to 3 cycles. Antiemetic medication including a selective 5-hydroxytryptamine-3 (5HT3) antagonist and steroids was routinely prescribed intravenously for all chemotherapy cycles. The patients in the study group received celecoxib 100 mg twice a day from the first day of concurrent chemoradiation until 3 weeks after the last cycle of adjuvant chemotherapy (18th week). The patients in the control group received placebo with the same schedule as the study group [Figure - 1]. Clinical response rates and safety were the primary and secondary endpoints, respectively. Before starting therapy, all the patients were asked about any history of allergic reaction to nonsteroidal anti-inflammatory drugs, celecoxib intolerance, uncontrolled hypertension, gastrointestinal bleeding, gastrointestinal ulcer, hepatic and/or renal dysfunction, and/or insufficiency. All the patients were examined with special attention on the status of the cervical lymph nodes regarding the location of the involved nodes, and their sizes, consistency, and fixation. Location, size, and extension of the primary tumor and the cervical lymph nodes were assessed by magnetic resonance imaging (MRI) and computed tomography (CT) scans. Stages were assigned according to the 6 th edition of the American Joint Committee on Cancer (AJCC) TNM 2002 staging system. The patients' functional statuses were evaluated according to the Karnofsky performance status. Chest radiograph and laboratory tests, including complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactic dehydrogenase (LDH), liver function tests (LFT), and renal function tests (RFT) were obtained from all the patients. A whole body bone scintigraphy was performed in symptomatic patients or those with elevated alkaline phosphatase level. After completion of concurrent chemoradiation, all the patients from both groups were followed and evaluated during the rest of the treatment every 3 weeks before every adjuvant chemotherapy administration. At the end of intervention (18th week), new evaluation, including CBC, ESR, LDH, LFT, RFT, and MRI and CT scan of the primary site and neck were performed for all the patients. The patients were followed weekly during the first 7 weeks of treatment, before every concurrent cisplatin infusion. They were examined every week and the changes of their lymph nodes and Karnofsky performance statuses were evaluated. Grades of mucositis and dermatitis were determined based on the Radiation Therapy Oncology Group (RTOG) scoring criteria. CBC, ESR, LDH, LFT, and RFT were checked weekly. The grades of the hematologic toxicities were also determined based on the RTOG scoring criteria. Complete response was defined as complete (100%) clinical and radiologic disappearance of the tumor. Partial response was defined as incomplete (less than 100% but more than 50%) clinical and radiologic shrinkage of the tumor. Less than 50% clinical and radiologic shrinkage of the tumor was considered as no response. Assessment of clinical response rates was performed 18 weeks following the first day of RT. A minimum sample size required 24 patients in each arm to ensure 80% power at the 5% significance level for detecting a 40% improvement in the clinical complete response rate from 30% to 70%. The survival durations were calculated from the date of RT start till the events of treatment failure (locoregional control), death from any reason (overall survival) or the last follow-up. The significance of differences in survival was evaluated using the log-rank test. The Chi-squared (χ2 ) test, Fisher's exact test, and Mann-Whitney test were used for comparing the clinical response rates and the clinicopathologic characteristics of the groups. Analysis for disease-free survival and overall survival rates was performed using the Kaplan-Meier method, and prognostic factors were compared using the log-rank test. P values less than 0.05 were considered significant. Results After excluding 3 patients who developed skeletal metastases or refused chemotherapy, 50 patients were evaluable (25 patients in each group). The mean age was 42 years (range 18-69 years) in the study group, and 44 years (range 18-65 years) in the control group. In each group, 15 patients (60%) were men and 10 (40%) were women. Thirty-five patients (70%) presented with stage III disease and 30% had stage IV disease. The median dose of radiation was 70 Gy (range 60-70 Gy) in both groups. In addition all the patients received a median 5 cycles of weekly cisplatin (range 4-7 cycles); and a median 3 cycles of adjuvant chemotherapy (range 2-3 cycles) [Table - 1]. Overall clinical response rate was 100% in both groups. Complete and partial clinical response rates were 64% and 36% in the study group, and 44% and 56% in the control group, respectively (P > 0.25). Patients with partial response had suspected (7 in study group and 10 in control group) or obvious (2 in study group and 4 in control group) residual disease at primary site on imaging. Those with obvious residual disease underwent direct nasopharyngoscopy for accurate clinical evaluation and pathologic confirmation. Among these patients, pathologic examination revealed viable residual disease in 2 patients of the control group, and only necrosis and inflammation in the remaining 4 patients. For patients with partial response and suspected residual disease, a follow-up imaging (MRI and CT scan) was performed 3 months later. All of the 17 patients had normal follow-up imaging without evidence of abnormal finding that favors residual disease. Therefore, when considering these results, the ultimate complete response rates were increased from 64% to 100% in the study group, and from 44% to 92% in the control group at the end of the 30 th week. During the follow-up period 12 patients experienced recurrent disease (8 cases with isolated skeletal relapse and 4 cases with locoregional and skeletal failure). After a median follow-up of 26 months (range 21-31 months) for surviving patients, 38 patients are alive and without disease, 5 (2 of the study group and 3 of the control group) are alive with disease and 7 (3 of the study group and 4 of the control group) died due to disease. We found a significant improvement in 2-year locoregional control rate in the study group when compared with the control group (100% vs. 84%, P = 0.039). However, 2-year overall survival was not significantly different by treatment groups (88% vs. 84%, P = 0.698). In addition, there was no significant association between the stage of disease and complete response rate (P > 0.15). All the patients well tolerated concurrent chemoradiation and adjuvant combined chemotherapy regimen. Acute treatment-related toxicities were manageable in both the groups. The patients in study group tolerated celecoxib well, and none of them had significant complaint of side effects. Anorexia, nausea, pharyngitis, fatigue, vomiting, xerostomia, and dermatitis were the most frequent treatment-related toxicities in both groups. None of patients developed grade 4 toxicities, and treatment-related death was not observed. One patient in the study group developed profound hypokalemia (2.1 mmol/L) 2 weeks after the third cycles of adjuvant chemotherapy (17th weeks). Another patient in the study group developed lung abscess 4 weeks after the third cycles of adjuvant chemotherapy (19th weeks). All the patients in both the groups were managed well, with a similar rate of late sequelae. Xerostomia, soft tissue fibrosis, otitis media, dental caries, and hearing loss were the most frequent late complications in both arms [Figure - 2]. There was no significant difference in terms of acute treatment-related toxicities between the 2 groups. [Table - 2] shows the frequency of acute treatment-related toxicity rates of the 2 groups. Discussion There are increasing evidences of the superiority of concurrent chemoradiation compared to radiotherapy alone in patients with locally advanced nasopharyngeal carcinoma. According to these evidences, concurrent chemoradiation with cisplatin-based regimen with or without neoadjuvant or adjuvant chemotherapy is currently considered the standard of care for locoregionally advanced nasopharyngeal carcinoma. Despite this improvement, outcome of patients with locally advanced nasopharyngeal carcinoma remains poor. [1,2] Therefore, novel antineoplastic agents need to receive more attention. One of the most promising agents is COX-2 inhibitors, which are under investigation for improving the response to radiotherapy and chemotherapy. COX-2 inhibitors, such as celecoxib, may have a role in the treatment of cancers via inhibiting cellular proliferation and angiogenesis, decreasing distant metastases, and inducing apoptosis. [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] COX-2 enzyme overexpresses in many different tumors, and its role in tumorigenesis, angiogenesis, transformation, and metastasis has been shown in several studies. [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] Many studies assessed the prophylactic role of COX-2 inhibitors in various tumors, such as colon and breast cancer, and showed that nonsteroidal anti-inflammatory drugs and COX-2 inhibitors decrease the incidence of colon and breast cancer via inhibiting cyclooxygenase-1 and -2 enzymes. [3],[4] Lee et al. showed that COX-2 enzyme was overexpressed in cultured cells of squamous cell carcinoma of the head and neck, when compared with normal cells. The authors concluded that COX-2 inhibitors significantly decreased cell growth and increased apoptosis in cultured cells. [5] This study and several others have shown that COX-2 inhibitors may have chemopreventive and therapeutic effects in squamous cell carcinoma of the head and neck. [5],[6],[7],[8],[9] In another study, Soo et al. found celecoxib 400 mg twice daily for 14 days reduced microvessel density and induced changes in gene expression in patients with newly diagnosed, untreated nasopharyngeal carcinoma. [6] In addition, several studies found that COX-2 inhibitors significantly enhanced the response of tumor cells to radiotherapy. The exact mechanism(s) responsible for the antiproliferative effect of COX-2 inhibitors remains to be defined; however, antiangiogenic effects of COX-2 inhibitors seem to be mainly responsible for increasing the antitumor effects of ionizing radiation. [10] Therefore, COX-2 inhibitors have a potential role for improving response to radiotherapy. [10],[11],[12],[13],[14] Several clinical trials studied the role of COX-2 inhibitors in improving response to radiotherapy or chemotherapy in many different cancers, such as head and neck and breast cancer. Despite promising results in preclinical studies, most clinical studies showed that COX-2 inhibitors have had no effect on response or survival rates in patients. [3],[4],[5],[6],[8],[9],[13],[14] In a phase I-II trial at Princess Margaret Hospital, the toxicity and efficacy of celecoxib in combination with definitive chemoradiation were evaluated in 31 women with locally advanced cervical cancer. All the patients received oral celecoxib 400 mg twice daily for 2 weeks before and during chemoradiation. They found acute grade 3/4 hematologic and gastrointestinal toxicities were the most frequent and were largely attributed to chemotherapy. Twenty-five of 31 patients (81%) achieved complete response during the first year of follow-up. The authors concluded that definitive chemoradiation in combination with celecoxib was associated with acceptable acute toxicity, and higher than expected late complications. They found the addition of celecoxib to definitive chemoradiation did not improve tumor response. [16] Another phase II trial studied response rate, toxicity, and overall survival rates in patients with potentially resectable esophageal cancer. Thirty-one patients received neoadjuvant chemoradiation with cisplatin and 5-FU plus celecoxib 200 mg twice daily on day 1 until surgery and then at 400 mg twice daily until disease progression or unexpected toxicities, or for a maximum of 5 years. The patients underwent esophagectomy 4-6 weeks after completion of chemoradiation. Most patients experienced grade 3/4 toxicities, of which diarrhea, neutropenia, nausea/vomiting, esophagitis, dehydration, and stomatitis were most frequent. There were 7 treatment-related deaths. [3] Of 22 patients who underwent esophagectomy, 5 had pathologic complete response (22%). The authors concluded that the addition of celecoxib 400 mg twice daily to chemoradiation was well tolerated, however, the pathologic complete response rate of 22% in their study was similar to that reported with the use of preoperative chemoradiation alone in other trials. [17] Recently, few studies evaluated the efficacy and safety of concurrent chemoradiation with weekly cisplatin in patients with nasopharyngeal carcinoma. These studies concluded that this treatment approach is safe and effective for most patients with nasopharyngeal carcinoma even in the elderly patients. [21],[22],[23],[24] The present study is the first clinical trial evaluating the efficacy and safety of low-dose (100 mg twice daily) celecoxib with concurrent chemoradiation plus weekly cisplatin in locally advanced undifferentiated nasopharyngeal carcinoma. Consistent with the recent studies, this study confirmed the safety and efficacy of this treatment for patients with locally advanced undifferentiated nasopharyngeal carcinoma. [21],[22],[23],[24] The addition of celecoxib 100 mg twice daily did not change the rates of overall survival or treatment-related acute toxicities, however, it significantly improved locoregional control rate, which is a promising point that should be evaluated in future studies using higher doses of celecoxib. The incidence of severe treatment-related toxicities was infrequent and most patients well tolerated the treatment. In this study, 1 patient developed severe hypokalemia, a complication of cisplatin-based chemotherapy that was rarely reported in the literature. [25] The rather high incidence of skeletal metastases in this study may be attributable to the suboptimal or ineffective adjuvant systemic chemotherapy and/or aggressive behavior of this neoplasm. In any case, this highly suggests the need for a more effective systemic treatment in these patients. The use of more effective chemotherapeutic agents, such as taxane-containing regimen, particularly in neoadjuvant setting, may further improve locoregional control and survival in patients with locally advanced undifferentiated nasopharyngeal carcinoma. [24],[26] There is no evidence in phase I or phase II clinical trials defining radiosensitizing dose for celecoxib. In recent few phase I clinical trials an escalating dose (100-400 mg, twice daily) has been used. [27],[28] The rationale for this lower dose administration of celecoxib was to evaluate the radiosensitizing effect of lower dose of celecoxib, rather than antitumor and antiangiogenesis effects. Most other studies, however, despite using higher doses of celecoxib, failed to show any survival benefit for the addition of celecoxib. [29],[30],[31] Conclusions Concurrent chemoradiation with weekly cisplatin followed by adjuvant combined cisplatin-based chemotherapy is highly effective in locally advanced undifferentiated nasopharyngeal carcinoma. The addition of celecoxib 100 mg twice daily to concurrent chemoradiation improved 2-year locoregional control rate, however, its effect on the response rates, treatment-related toxicities and overall survival was not statistically significant. Acknowledgment This clinical trial was approved and supported by Shiraz University of Medical Sciences as research number project 2664. In addition, the study was registered on the clinical trials registration website of Australia and New Zealand (ANZCTR) on 12 October 2008 (number: ACTRN12608000449336). References
Copyright 2011 - Journal of Cancer Research and Therapeutics The following images related to this document are available:Photo images[cr11118t1.jpg] [cr11118t2.jpg] [cr11118f2.jpg] [cr11118f1.jpg] |
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