Concurrent chemo-radiotherapy is considered the standard treatment for patients affected by locally advanced, stage III, unresectable Non-Small Cell Lung Cancer (NSCLC) and good performance status (PS) [
1]. Stage III NSCLC constitutes a heterogeneous group, likely due to a different nodal involvement; its median survival has been recently updated from 12 to 23.3 months in phase III trials [
2,
3]. The recommended systemic treatment in stage III NSCLC consists of 2–4 cycles of platin-combination with concurrent radiotherapy [
4]. In an effort to improve overall survival (OS) different schemes for both induction and consolidation therapy are used in clinical practice, with induction chemotherapy before the start of concurrent chemo-radiotherapy preferred by some [
2,
5] and consolidation modalities preferred by others [
3,
6]. However, no clear superiority has been demonstrated between those two approaches. Docetaxel enhances the cytotoxic effects of radiotherapy in vitro [
7]. In several phase II studies radiotherapy with concurrent Docetaxel and after induction with Cisplatin-Docetaxel combinations has been shown to be feasible [
8,
9], with encouraging OS rates. There is an indication that higher radiation doses may result in improved probability of local tumour control [
10]; however, using current radiation delivery techniques dose escalation, in particular in combination with chemotherapy, may lead to unacceptable lung toxicity. Therefore, the search for better radiotherapy approaches is important and Tomotherapy (HT) may be one of the most promising technologies for this purpose [
11]. HT is a novel technique, which allows the delivering of Image Guided - IMRT (IG-IMRT), by using a dynamic delivery in which gantry, treatment couch, and multileaf collimator leaves are all in motion during treatment, resulting in a highly conformal radiation dose distribution [
12]. The development of those techniques has led to improved radiation delivery with better tumor coverage and decreased exposure of surrounding normal tissues; however, in the CALBG 30105 study [
13] the arm with Gemcitabine concurrent with high dose conformal radiation treatment was closed for high rate of severe pulmonary toxicities, likely due to larger mean lung doses; however the authors suggest that radiosensitizing properties of Gemcitabine on normal tissue may have contributed to the higher pulmonary toxicity observed [
14]. On this basis, we were concerned that, using a radiosensitizer agent such as Docetaxel concurrent with Tomotherapy, with larger volumes of healthy lung treated with low dose radiation, could lead to a different maximum tolerated dose (MTD) for Docetaxel.
We designed a phase I, dose-finding study to estimate the tolerability of concurrent Docetaxel with Tomotherapy and to determine the MTD of weekly Docetaxel concurrent with IMRT delivered with HT after induction chemotherapy. We chose to study Docetaxel alone combined with concurrent HT, because Docetaxel may enhance both activity and toxicity of radiotherapy and we did not want to have any confounding bias in the results analysis. For this reason we chose to deliver the backbone of systemic treatment for NSCLC, i.e. platinum, in the induction part, using Docetaxel alone in the concurrent study.