Clinical Application Of Intensity Modulated Radiotherapy With Accelerated Fractionation In Nasopharyngeal Carcinoma And Study Of Neoadjuvant Chemotherapy

Part Ⅰ:Clinical efficacy of intensity modulated radiotherapy with accelerated fractionation in patients with nasopharyngeal carcinomaBackground:Nasopharyngeal carcinoma (NPC) arises from the epithelia of the nasopharynx, moderately sensitive to radiation. The local residual rate of NPC is about 10% and local recurrent rate ranges from 16.8-23%, depending on the initial tumor status. Accelerated proliferation of clonogenic tumor cells is the main reason for radiotherapy failure. Longer courses of treatment cause an increase in proliferating cells under certain total dose. To extend radiotherapy one day requires an additional 0.66 Gy to offset tumor cell proliferation for Tpot=3d cancer. Using conventional radiotherapy, the efficacy of six times weekly group was significantly better than the efficacy of five times weekly group. With the intensity modulated radiotherapy (IMRT) technology widely used, a single dose of radiation is improved, the total course should be shortened corresponding. This acceleration segmentation model has been widely recognized in clinical. How is the efficacy and toxicity to increase the fractionation number of IMRT weekly, and no corresponding literature.Introduction:The purpose of this study was to analyze the efficacy and safety of IMRT with accelerated fractionation (Six times weekly) in patients with NPC.Methods:This study included 89 NPC patients treated with six fractions of IMRT per week. The IMRT doses were planning target volume (PTV) 68-72 Gy for gross disease in the nasopharynx, and 66-70 Gy for positive lymph nodes in 33 fractions. The doses for high risk and low risk region PTV were 62 Gy in 33 fractions and 52 Gy in 28 fractions. For the end of radiotherapy residual cervical lymph node were pushed on 2-6Gy using 9Mev electron beam. Concurrent with chemoradiotherapy, stage Ⅲ/Ⅳ NPC patients received a chemotherapy program consisting of Cisplatin 75 mg/m2, day 1. The cycle repetition was every 21 days. The Kaplan-Meier test was used to calculate overall survival (OS), distant metastasis-free survival (DMFS), local-regional control (LRC) and progression-free survival (PFS). Relevant factors were screened using a chi-square test, and independent risk factors were analyzed using the Cox proportional hazards model.Results:The 3-year OS, DMFS, LRC and PFS were 83.6%,80.2%,94.4% and 75.7%, respectively. No regional lymph node recurrence was detected. Further analyses revealed that gender, age, anaemia, T stage, tumor diameter≥2.5cm, the level of EBV-DNA, regularity of radiotherapy and severe radiotherapy complication were not significantly associated with the prognosis of patients (all P> 0.05). N stage (P=0.002, HR=9.526,95% CI=1.305～3.327) were independent prognostic factors for DMFS, clinic stage (P=0.003, HR=9.557,95% CI=1.713～11.194) was independent prognostic factors for OS. The median recurrent time was 31 months (range,23-50 months). The median distant metastasis time was 11.5 months (range, 3-38 months). The most serious acute toxicity was mucositis, with prevalence of Grades 0 to Ⅳ being 2.2%,27.0%,47.2%,20.2%, and 3.4%, respectively. Late toxicity manifested as Grades Ⅰ and Ⅱ xerostomia in 59 and 18 patients.Conclusion:In patients with NPC, IMRT with accelerated fractionation yielded an excellent local control rate, and the toxicities were mild and tolerable. Distant metastasis was the main cause of treatment failure.Part Ⅱ:Docetaxel combined with lobaplatin neoadjuvant chemotherapy followed by concurrent lobaplatin with intensity modulated radiotherapy increases the efficacy of patients with high-risk nasopharyngeal carcinomaBackground:Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with high incidence in Southeast Asia. In recent decades, great advancements have been made in NPC treatment, including the renewal of radiotherapy technique and the replacement of chemotherapy drugs. Therefore 5-year local control rate of locally advanced NPC was raised to 90%,5-year overall survival rate was more than 80%, but still 15-25% of distant metastasis rate did not improve. Currently it is the hot and difficult research how to improve the rate of distant metastasis-free survival (DMFS). The lymph node stage was the most important prognosis factor affecting DMFS. High risk factors of NPC distant metastasis include T4N2, N3 and in multiple lymph nodes, at least one lymph node diameter> 4 cm. Neoadjuvant chemotherapy can reduce subclinical metastases by killing tumor cells in circulation.Purpose:To evaluate the efficacy and safety of docetaxel combined with lobaplatin as neoadjuvant chemotherapy followed by concurrent lobaplatin with intensity-modulated radiotherapy (IMRT) for high-risk positive lymph node (N+) nasopharyngeal carcinoma (NPC).Methods:This study enrolled 37 primary high-risk N+NPC patients. The neoadjuvant chemotherapy program was docetaxel (75 mg/m2, day 1,ivgtt) plus lobaplatin (30 mg/m2, day l,ivgtt) for two cycles. Concurrently with IMRT, patients received a chemotherapy program of lobaplatin (50 mg/m2, day l,ivgtt), Cycle repetition was every 21 days. The IMRT doses were planning target volume (PTV) 70-74 Gy for gross disease in the nasopharynx, and 66-70 Gy for positive lymph nodes in 33 fractions. The doses for high risk and low risk region PTV were 62-64 Gy in 33 fractions and 52-56 Gy in 26-28 fractions. For the end of radiotherapy residual cervical lymph node were pushed on 2-6Gy using 9Mev electron beam. The Kaplan-Meier method was used to calculate OS, DMFS, LRFS and PFS. Comparisons of the frequency of data between groups were carried out using the chi-square test.Results:The median follow-up duration was 31 months (range 4-52). The 3-year overall survival (OS) was 74.3%. The 3-year distant metastasis-free survival (DMFS) was 67.4%. The 3-year locoregional relapse-free survival (LRFS) was 91.5%, and the 3-year progression-free survival (PFS) was 61.2%. The efficiency of short-term effects of neoadjuvant chemotherapy and chemoradiotherapy were 83.8% and 100.0%, respectively. The most serious acute adverse reactions of radiation is radiation mucositis, with Ⅰ level 14 (37.8%), Ⅱ level 18 (48.6%), Ⅲ level 4 (10.8%). Hematologic toxicity was well tolerated. Its toxicity mainly as leukopenia (97.3%), thrombocytopenia (83.8%) and anemia (81.1%). The main reason for treatment failure is distant metastasis, the most common site of metastasis is bone, the median time to distant metastasis was 10 months (3-31).Conclusions:In patients with high-risk NPC, docetaxel combined with lobaplatin neoadjuvant chemotherapy followed by concurrent lobaplatin with IMRT yielded excellent short-term results with mild and tolerable toxicities.