Study On The Influence Factors Of Long-term Survival Of Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is the most common malignant tumor originated in the nasopharyngeal stenosis cavity. NPC is low incidence In western countries, however, it is very popular in southern China and countries (regions) of Southeast Asia. NPC is one of the main diseases threatening people’s health in our country in a long time, and also is one of three malignant tumors of China’s southern male inhabitant. It has an incidence rate of15-50/100,000in men in these areas. More importantly, NPC often occurs in middle-aged men which seriously affected the social labor resources.Surgical resection of NPC is very difficult for the reason of special anatomic site, therefore, the mainstay strategies for the treatment of NPC are radiotherapy-based, comprehensive therapies, including chemotherapy. However, many factors influenced the curative effect and prognosis of NPC, such as age, gender, race, clinical stage, histological type, original treatment methods and salvage treatment or not, etc. All of above Interlocking factors brings difficulties to our curative effect and prognosis judgment. For this purpose, we performed this retrospective study which included the clinical data of all NPC patients who were newly diagnosed and treated in Macao Special Administrative Region between2005and2009, in order to obtain a more accurate judgments to curative effect and prognosis of different stage NPC.PART I Multivariate Analysis of Long-term Follow-up Result of Nasopharyngeal CarcinomaObjective Nasopharyngeal carcinoma is a common malignancy in Southeast Asia, especially in the southern coastal area of Mainland China and in Hong Kong, Macao and Taiwan. However, the epidemiological characteristics of NPC are significantly different from those in low incidence regions. The therapeutic method and prognosis of Asian are different from that of Western either. Full consensus has not been reached regarding the value of comprehensive treatment. This study was designed to evaluate the epidemiological characteristics and long-term treatment efficacy in patients with NPC in Macao and to analyze the clinicopathological prognostic factors.Patients and MethodsThis retrospective study includes the clinical data of all NPC patients who were newly diagnosed and treated in Macao Conde S. Januario General Hospital between2005and2009. Patients that had been previously diagnosed with NPC and treated, but who had relapsed during this period, were excluded. However, the study did include patients that had been diagnosed with NPC outside of Macao during that time, who then underwent subsequent treatment and follow-up at Conde S. Januario General Hospital. Data collected included patient demographics, NPC stage, histological type, treatment modalities, treatment efficacy, and survival time. Patient demographic characteristics included gender, age, and marital status.The treatment modalities were radiotherapy alone, neoadjuvant chemotherapy followed by radiotherapy, concurrent chemoradiotherapy plus adjuvant chemotherapy, or palliative treatment. Palliative treatment of advanced tumors included single-agent chemotherapy or combined chemotherapy and radiotherapy.Examinations included a complete medical history and physical examination, a craniofacial examination (including dental and cranial nerve exams), nasopharyngofiberscopy, a complete blood count, serum biochemistry, a chest X-ray, and a CT or MRI examination of the nasopharynx, skull base and any suspicious metastatic sites, including the paranasal sinuses.Prognostic factors for NPC patients were determined by analyzing the associations between patient survival and the following:age, gender, disease-stage, NPC histological type, treatment modalities and primary therapeutic effects. The Kaplan-Meier method was used for survival analysis. The survival curves between groups were analyzed using the Log-rank test. The main prognostic factors were analyzed using the Cox proportional hazards model.ResultsA total of248patients with NPC, at all stages, were included in this study. The median age was49.0years old and the ratio of males to females was184:64. The median follow-up time was47.5months (range:1-109months). Among the patients,91.13%were of Type III according to WHO classification. Patients in stage I according to the American Joint Committee of Cancer (AJCC) accounted for only8.47%of the total, while patients in stages III and IV of the disease accounted for59.7%.The5-year survival rate for all patients that underwent follow-up was68.70%, however, the median survival (5-year) was not reached and could not be calculated. The5-year survival rates for patients in stages I-IV were90.48%,76.71%,76.89%and33.87%(P=0.000), respectively. The5-year PFS rate was61.04%for all patients. Just like the median survival, the median PFS (5-year) was not reached either, while the5-year progression-free survival rates were85.15%,72.36%,63.88%and26.26%(P=0.000), respectively.The5-year survival rates in the group that received radiotherapy combined with chemotherapy and in the group that received only radiotherapy were as follows:Stages Ⅰ and Ⅱ:81.67%and79.59%(P=0.753), stage Ⅲ:79.91%and70.38%(P=0.143), and stage Ⅳ:35.22% and0%(P=0.000), respectively, Only the patients of stage IV had significant difference. The5-year progression-free survival rates in these two groups were as follows:Stages Ⅰ and Ⅱ:75.83%and74.98%(P=0.814), stage Ⅲ:74.08%and42.25%(P=0.027), and stage Ⅳ:27.31%and0%(P=0.000), respectively. Both stage Ⅲ and stage Ⅳ had statistics difference.ConclusionsCompared with other clinicopathological parameters, AJCC staging in NPC patients is the most important prognostic factor. As the stage number increases, the5-year survival rates and5-year progression-free survival rates are both significantly reduced. For patients in the early or mid stage (Ⅰ-Ⅱ), there is no advantage of adding chemotherapy to radiotherapy, however in patients with advanced (stage Ⅳ) NPC, the addition of chemotherapy significantly improves overall and progression-free survival compared to radiotherapy alone. For patients with locally advanced (stage Ⅲ) NPC, addition of chemotherapy improves progression-free survival, but not overall survival. PART Ⅱ Retrospective Study of the Effect of Adjuvant Chemotherapy in Intermediate andLocoregionally Advanced Nasopharyngeal CarcinomaObjectiveFor early stage Nasopharyngeal Carcinoma, the standard therapeutic scheme is radiotherapy alone; while for advanced NPC, the current standard treatment is composed of irradiation and cisplatin-based systemic therapy.Concurrent chemoradiotherapy (CCRT) showed a significant improvement in disease control and clinical outcome in patients with intermediate and locoregionally advanced nasopharyngeal carcinoma (NPC)(stage II, III and IVA+B). However, there has been debate about the contribution and application of additional adjuvant chemotherapy (AC) to CCRT regime. This study aims to evaluate the additional value of AC to the treatment of intermediate and locally advanced NPC with regard to toxicity and clinical outcomes.Patients and MethodsFrom May2003through to April2007,189patients with biopsy-proved, intermediate and locoregionally advanced (stage II to Stage IVB) NPC finished CCRT schedule with/without followed by AC at the Department of Haemato-oncology, Conde S. Januario General Hospital, Macao SAR of China. All cases must have received CCRT, part of them had also received AC after radiation. All patients in the two groups had received intensity-modulated radiation therapy (IMRT) from Monday to Friday, with a dose range from62to70Gy (median66Gy). Of all studied patients,96received CCRT after diagnosed; and93received CCRT and followed by AC. The chemotherapy during CCRT consisted of weekly cisplatin (30mg/m2) for6to8weeks. Three cycles of AC were given with cisplatin (80mg/m2) and5-FU (1000mg/m2/d on day1to4) every4weeks to patients of CCRT/AC arm.Clinical records and radiographic study of the patients were reviewed retrospectively. Documented data of the initial presenting symptoms, head and neck examination, radiotherapy protocols, chemotherapy treatment regimens were analyzed. Pretreatment evaluation consisted of a complete history, physical examination including cranial nervous function test, fiberoptic nasopharyngoscopy, complete blood cell count, serum biochemistry (including liver and renal function test), chest X-ray, computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the nasopharynx and base of skull and neck, dental evaluation. The imaging of distant metastases including isotope bone scan and CT scan of the upper abdomen and chest could be considered for at-risk subsets presented (lymph node positive, especially N3stage) and for those patients with clinical indication.Response was assessed three months after the completion of radiation in the CCRT group and two weeks after the last chemotherapy in the CCRT/AC group. The evaluation standard was in accordance with the WHO response criteria and included CR, partial response (PR), no change (NC) and progressive disease (PD). Clinical characteristics, flexible nasopharyngoscopy and radiological examination (CT or MRI scan) were evaluated at every visit. The toxicity caused by chemotherapy and/or radiotherapy was also assessed in accordance with the WHO standard.Each patient was evaluated every week during CCRT. When radiation was finished, all cases were assessed every three months during the first two years and then every half year until death. Patient characteristics, toxicity, compliance with treatment and clinical outcomes including response to treatment, overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), freedom from local recurrence survival (FLRS), and freedom from distant metastasis survival (FDMS) were analyzed.The primary end point of the study was to compare OS at5years in the two groups. The other goals were to assess and compare the objective response rate, toxicity, relapse-free survival (RFS), freedom from local recurrence survival (FLRS), and freedom from distant metastasis survival (FDMS) rates in both arms. The Kaplan-Meier product-limit method was used in the calculation of OS, RFS, FLRS and FDMS rates. The significance of differences between survival curves was estimated by Log-rank test. Hazard rations and CIs were estimated for various end points. Toxicity rates were compared using χ2test.ResultsThe median follow-up duration of the CCRT and CCRT/AC patients was49months (range,6to82months) and41months (range,3to82months), respectively. During the treatment of CCRT, patients were evaluated every week. After completion of radiation, patients were evaluated every four weeks for the started half year, and every three months until the end of two years, then every six months thereafter.The five-year OS rate for the189patients was71.45%, and five-year PFS rate was70.31%. The overall response rate of CCRT and CCRT/AC groups was97.92%and97.83%, respectively (P=0.643). Five-year OS rate was68.2%in CCRT group and75.9%in CCRT/AC group (P=0.53). Neither group reached the median OS duration (50%) due to the long survival time. When we analyzed the data,30patients had died in the CCRT group, and21patients had died in the CCRT/AC group. Five-year PFS rate was66.7%and71.4%in CCRT and CCRT/AC groups, respectively (P=0.96).The5year RFS rates were66.6%for CCRT group compare with80.1%for CCRT/AC group; this difference was no statistical significance (P=0.39). The5-year FLRS rates were88.6%for the CCRT group and94.6%for the CCRT/AC group (P=0.48). The5-year FDMS rates were75.2%for the CCRT group and84.7%for the CCRT/AC group (P=0.57). No statistically significant difference was found in RFS, FLRS or FDMS between the two groups.Grade4(life-threatening) toxicity occurred in eleven patients, and39patients had grade3(severe) side effects from adjuvant chemotherapy. A relative high incidence of grade3or4leukopenia, nausea, vomiting and stomatitis was observed in this group. Twelve went off permanently due to toxicity. Two refused further treatment after completed first cycle of chemotherapy, documented as unrelated to toxicity. One patient was off for died from severe infection during the second cycle of adjuvant chemotherapy and was defined as fatal toxicity related case. So only83.9percent of patients received all three courses of AC finally. ConclusionsResults of this study showed that with or without AC after CCRT had no effect to OS and PFS in both groups, that is to say no evidence of additional value of AC to CCRT treatment in disease control and clinical outcomes in patients with locally advanced NPC in endemic region. Moreover, additional three cycles of AC after CCRT seems poorly tolerated in patients. About16.1percent of patients in AC group had to finish schedule for could not tolerate the adverse reaction. So it cut down the quality of life and compliance. Therefore, AC should not be used routinely after CCRT except for a clinical trial.