Metronomic Chemotherapy Combined With Radiotherapy In Locoregionally Mid-late Stage Nasopharyngeal Carcinoma:Cisplatin Dose, Tolerability And Efficacy

Objective:Metronomic chemotherapy is a therapeusis with low dose of traditional chemotherapeutics, It is demonstrated by research that taking tumor vessel as the target, this therapy strategy has obvious anti-angiogenesis effect. Basic and clinical trials confirmed that metronomic chemotherapy combined with radiotherapy can improve the effect of the radiation therapy, and not increase the radiation toxicity. Nasopharyngeal carcinoma is one of the common malignant tumors in China and radiation therapy is the main treatment of it. However, most of patients are in the later stage at the time of diagnosis, radiotherapy alone cannot reach the certain treatment strength and then need the comprehensive treatment with chemotherapy、anti-angiogenesis therapy and so on. In recent years, the NCCN clinical practice guidelines in head and neck cancer recommend that40mg/m2/week of cisplatin combined with radiotherapy for Locoregionally mid-late stage nasopharyngeal carcinoma, this strategies has been widely used in clinical. But an important question of this strategy is that a large proportion of patients are difficult to tolerate the full course of treatment due to severe oropharyngeal mucosa, skin, gastrointestinal toxicity, resulting in treatment interruptions that may affect the treatment efficacy. This study based on the antiangiogenic effect of metronomic chemotherapy and its relative low toxic-side effects, by means of combined cisplatin metronomic chemotherapy with radiotherapy for treatment of locoregionally mid-late stage nasopharyngeal carcinoma, to explore the phase I clinical dose of cisplatin in this treatment model and its clinical effect and patient’s treatment tolerance.Methods:Since February2011to December2011, it has been selected suitable22cases about the nasopharyngeal carcinoma patient in my department. Among them15cases are divided into group which is treated with metronomic chemotherapy and radiotherapy combined treatment (called as the "metronomic chemotherapy group" in this research) while7cases are divided into radiotherapy alone group (called as "control group" in this research). In metronomic chemotherapy group, according to phase I clinical trial of anti tumor drug, we set3mg/m2as the starting dose of cisplatin metronomic chemotherapy, and20mg/m2as the maximum dose, performed dose-climbing experiment of cisplatin acccording to modified Fibonacci method by increasing cisplatin dosage form3mg/m2, twice a week, combined radiotherapy to treat III, IVa, IVb phase nasopharyngeal carcinoma at the same time. We searched the dose limited toxicity (DLT) and maximum tolerance dose (MTD) of cisplatin in metronomic chemotherapy group, and evaluated the compliance of patients. Patients in control group are treated with radiotherapy alone. We compared the early toxicity, treatment tolerance, Short-term effect and long-term toxicity of two groups, and did3times CT perfusion scan before radiotherapy, radiotherapy40GY and after radiotherapy, in order to evaluate the microcirculatory change of tumor tissue, and to explore the antiangiogenic effect of cisplatin metronomic chemotherapy.Results:1. In the metronomic chemotherapy group, cisplatin dose-climbing experiment has been completed on3mg/m2、5mg/m2、8mg/m2and10mg/m2dose level. In the first three dose groups (3cases each group), none of them has III degree or above degree side-effect of concurrent chemoradiotherapy, then would be selected into next dose group. They have demonstrated good treatment tolerance. Three individuals were divided into10mg/m2dose group, a case of them has IV degree side-effect in the oropharyngeal mucosa and neck skin side-effect of grade III. According to the phase I clinical trial, to join other three cases of patients into the10mg/m2dose level experiment, finally, there was still one patient developed IV degree side-effect in the oropharyngeal mucosa and neck skin. Therefore, stopped the dose-climbing experiment and to determine oropharyngeal mucosa and neck skin toxicity as dose limited toxicity (DLT) of cisplatin metronomic chemotherapy combined with radiotherapy, and the maximum tolerance dose (MTD) for cisplatin metronomic chemotherapy in this treatment model is8mg/m2which is the prior dose of appearing dose limited toxicity.2. Compared the patients in15cases metronomic chemotherapy group with whom in7cases control group, there is no difference in clinical case characteristics between the two groups.15patients in the metronomic chemotherapy group have performed averagely11cisplatin metronomic chemotherapy administration with good compliance; and compared with the control group that has no statistic difference in short-term side-effect and long-term side-effect, no difference exists in weight-reduction and there are similarities in the short-term effect and treatment tolerance.3. CT perfusion scan results of the two groups shown that, after treatment, normal pharyngeal wall tissue perfusion parameters of two groups did not significant change, but BF, BV, PS measured values of nasopharyngeal carcinoma tumor showed a decreasing trend, MTT measurement was increasing. The reduction in the BF, BV, PS and increase in the MTT of metronomic chemotherapy group are greater than control group, however, only the difference of reduction in BV between the two groups reached the statistically significant.Conclusion:1. Maximum tolerance dose of twice-weekly cisplatin metronomic chemotherapy combined with radiotherapy in locoregionally mid-late stage nasopharyngeal carcinoma is8mg/m2. There are no obvious short-term and long-term side effects in this treatment model, it is effective and good compliance.2. Cisplatin metronomic chemotherapy showed the effect of anti-angiogenesis and improving microvascular function, it has synergistic and enhanced effect if combined with radiotherapy.