Accelerated Modulated Fractionation (SIB-IMRT) for the Treatment of Locally Advanced Squamous Cell Carcinoma From Head and Neck District
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Number of patients who experienced acute toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG / EORTC)
研究概览
简要总结
Nowadays the association between radiotherapy and the anti- Epidermal Growth Factor Receptor (anti-EGFR) monoclonal antibody Cetuximab represents a valid option in the treatment of head and neck locally advanced squamous neoplasm and, particularly, of oropharynx carcinoma. Up to date we have only indirect comparison with the standard curative treatment (i.e. concurrent radiochemotherapy) and the preliminary data show equivalent efficacy of both regimens. For this reason, concurrent Cetuximab and radiotherapy is administered in patients not eligible to chemoradiotherapy. The introduction of Cetuximab has been associated to new kind of toxicities, especially cutaneous, that have increasingly reported.
The aim of our study is to improve the toxicity/benefit ratio in patients receiving concurrent radiotherapy and cetuximab for locally advanced head and neck neoplasm. Hence, this improvement could be achieved by modulating radiation therapy dose per fraction following Cetuximab pharmacokinetics.
详细描述
Radiobiological rationale Overexpression of EGFR has been found to be involved into two different mechanisms of response to ionizing radiations: the former is related to the increased cell proliferation rate, the latter leading to lower radiosensitivity.
- Increasing of cell proliferation rate From an analysis of the already reported evidences, we quantified the effect of a higher cell proliferation rate due to overexpression of EGFR. These findings were reported in patients affected with squamous carcinoma of head and neck district and evaluated for EGFR status. In those patients, local recurrence was compared in patients with different length of treatment but at the same fractionation. Consequently, the real doubling time in the subgroups with high and low EGFR expression was extrapolated . From these extrapolated values, equivalent doses of each day of non-delivered treatment have been calculated for patients who received accelerated schedule. Furthermore, doses were reported in relation to the different primary sites (oropharynx, larynx, oral cavity, hypopharynx).
Modification of doubling time (TD) of neoplastic cell population in patients with Low and High EGFR expression. 2. Reduction of radiosensitivity Unfortunately, how radiosensitizing drugs can modify radiosensitivity cannot be evaluated retrospectively. Actually, the efficacy is evaluated on the basis of an overall effect of the treatment but radiosensitivity changes day by day in radiation and pharmacological concurrent treatment. However, these changing in radiosensitivity can be analysed in pre-clinical setting. In many reports, a progressively higher radiosensitivity has been shown in cellular survival curves by increasing EGFR inhibitor concentration. Nevertheless, the concentrations of EGFR inhibitor do not correspond to in vivo concentration during radiotherapy delivery. Fortunately, this data is obtainable from Cetuximab pharmacokinetic curve. Therefore, cell survival curves corresponding to drug concentration were obtained by performing a graphic interpolation. From these curves, daily radiosensitivity parameters were found.
Subsequently, daily doses with respect to daily radiosensitivity were identified by radiobiological calculation model. This fractionation, designed on Cetuximab pharmacokinetics, have been calculated to be equivalent to curative treatment (70Gy given with conventional schedule).
At the same time, lower cutaneous toxicity is expected with this "modulated" schedule due to the possibly increased cellular repair. Pharmacokinetics data of Cetuximab we found on the population: Vmax 4.38mg/h (15.4%), Km 74g/ml, central compartment volume Vl 2.83 l (18.6%), peripheral compartment volume 2.43 l (56.4%) and intercompartmental clearance 0.103 l/h (97.2%). Those parameters remain unmodified also during prolonged therapies. Administrated doses have been found to be adequate to cell wall receptors saturation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with histological proof of locally advanced squamous carcinoma of oropharynx, larynx, hypopharynx (stage III and Iva)
- •Overexpression of EGFR (>50%)
- •Patients previously considered non-eligible for curative radio-chemotherapy for clinical reasons.
- •Performance Status (ECOG) ≤ 2
- •Age ≥ 18 years
- •Possibility of correct administration of treatment
- •Written informed consent
排除标准
- •Distant metastases
- •Oral cavity or rhinopharynx neoplasm
- •Need of cutaneous bolus
- •Previous treatments on head and neck district
- •Collagenopathies or other severe systemic disease
- •Severe cardiopathies or myocardial infarction in the previous 12 months, serious hepatopathies or other diseases with heavy impact on general conditions.
- •Psychiatric disorders or other conditions preventing from expressing informed consent.
研究组 & 干预措施
Arm 1
Radiotherapy treatment associated with concurrent Cetuximab administration.
Patients candidate to curative concurrent Cetuximab and Radiotherapy are eligible for this study. After expressing written informed consent, patients will perform CT simulation. Then an IMRT-SIB (Simultaneous Integrated Boost) treatment plan will be elaborated and deliver the following Cetuximab pharmacokinetic:
Length: 6 weeks; 1 fraction daily (From Monday to Friday) 30 Total Fractions (5 per week, 6 weeks of treatment). Cetuximab will be administered weekly from a week before starting radiotherapy until the end of treatment for 7 subsequent administration accordingly to the standard schedule (1 before and 6 during radiotherapy).
干预措施: Cetuximab plus Radiotherapy (Drug)
结局指标
主要结局
Number of patients who experienced acute toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG / EORTC)
时间窗: up to 7 days during RT treatment
During radiotherapy, patients will be assessed weekly for acute toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale. Furthermore pain (NRS pain scale) nutritional assessment (weight in kilograms ) will be performed.
次要结局
- Number of patients who experienced local or distance recurrence of disease assessed through clinical and radiological controls(up to 6-8 weeks after treatment completion and then up to 2 years)
- Number of patients who experienced late toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale RTOG / EORTC(up to 6-8 weeks after treatment completion and then up to 2 years)