Docetaxel and Radiation as Combined-Modality Therapy

The treatment of solid tumors including non-small-cell lung cancer (NSCLC), head and neck cancer, and esophageal cancer continues to be challenging and associated with a poor overall survival. Traditional treatments have included single modalities such as surgery, radiation, or chemotherapy. Combined modality approaches offer a theoretical benefit by improving locoregional control and treating micrometastatic disease. Among the various chemotherapeutic agents administered concurrently with radiation therapy[1] are the platinums, taxanes, and gemcitabine(Drug information on gemcitabine) (Gemzar).[2-5] The taxanes, in particular, are active, tolerable drugs for the treatment of solid tumors, and they possess radiation-sensitizing activity. Docetaxel(Drug information on docetaxel) (Taxotere) has been studied in combination with radiation with favorable results. This report will focus on the treatment of solid tumors with docetaxel and radiation as combined-modality therapy.

Background

The taxanes are a class of antineoplastic agents, derived from plants, that have demonstrated efficacy in various malignancies.[6-9] Taxanes are potent mitotic spindle poisons that bind to beta-tubulin, increase tubulin polymerization, and promote microtubule assembly. The microtubules remain stabilized because the taxanes inhibit depolymerization.[10-15] The first taxoid was discovered in the 1960s when it was determined that the bark of the Pacific yew tree, Taxus brevifolia, had activity against several murine tumors. Paclitaxel(Drug information on paclitaxel) became the first commercially available taxane in 1992. Docetaxel, which was semisynthetically produced in 1986, is derived from 10-deacetyl-baccatin III, a noncytotoxic precursor extracted from the needles of the European yew, Taxus baccata. Docetaxel has several properties that are different from paclitaxel, including a higher uptake and accumulation in tumor cells and a greater affinity to microtubules.[16]

Preclinical Data

The radiation sensitizing effects of the taxanes are seen at drug levels well below those required for cytotoxicity. Studies of docetaxel have shown an enhanced response to radiation with induced mitotic arrest and apoptosis in murine tumor cells.[17,18] During the cell cycle, the G2/M phase has been found to be the most radiosensitive. Docetaxel exposure arrests cells in the G2/M phase, thus rendering them susceptible to radiation.[11,12,19-23] In addition, docetaxel induces apoptosis as well as direct cytotoxicity against radioresistant S-phase cells.[17,23] In vitro data have demonstrated the putative role of the taxanes in phosphorylation of the bcl-2 antiapoptotic oncoprotein, suggesting that these agents may further enhance the efficacy of radiation by facilitating the triggering of the apoptotic pathway after DNA damage by radiotherapy.[24]

The effects of the combination of docetaxel and radiation have suggested a synergistic effect on tumor cell radiosensitivity.[7,11,13,14] This synergy has been demonstrated in vitro as well as in vivo in murine models.[17] Docetaxel may also have immunomodulating properties as well as antiangiogenic effects.[25,26] Based on these preclinical results, phase I investigations of docetaxel with concurrent radiation therapy were initiated.

Phase I Trials

Multiple phase I trials have been conducted to assess the combination of single-agent docetaxel chemotherapy and radiotherapy in patients with non-small-cell lung cancer (NSCLC) and other solid tumors (Table 1).

Non-Small-Cell Lung Cancer

The Choy et al Trial

Choy et al[27] conducted a phase I study of weekly docetaxel with concurrent thoracic radiation therapy in patients with unresectable stage III NSCLC. Docetaxel was administered as a 1-hour infusion every week for 6 weeks at an initial dose of 20 mg/m², escalated in increments of 10 mg/m² as tolerated to each successive cohort of three patients. Thoracic radiation therapy was administered 5 days a week for 6 weeks to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor and involved nodes (20 Gy). A total of 15 patients (11 males and 4 females) with a median age of 61 years were enrolled in the study. Patients had stage IIIA (nine) or IIIB (six) disease and had a performance status of 0 or 1.

The principal dose-limiting toxicity was esophagitis and the maximum-tolerated dose of docetaxel with concurrent radiation therapy was 30 mg/m². Seven patients achieved a partial response for an overall response rate of 47%.

The Aamdal et al Trial

Aamdal et al[28] conducted a phase I study of docetaxel combined with radiation in 12 chemotherapy and radiotherapy-naive patients with inoperable stage III NSCLC. Docetaxel at 20 to 40 mg/m² was administered as a 1-hour infusion on days 1, 8, 22, and 29. Radiation therapy was administered in fractions of 2 Gy daily for 5 days over 5 weeks. The maximum tolerated dose of docetaxel was 40 mg/m² and the dose-limiting toxicity was reversible esophagitis-related dysphagia. The median survival was 15 months, with four patients still alive at 20 to 26 months’ follow-up. The recommended phase II dose was 30 mg/m² of docetaxel.

The Koukourakis et al Trial

A similar trial was conducted by Koukourakis et al,[29] who investigated the radiosensitizing effects of docetaxel and concomitant radiotherapy in 30 patients (all male) with advanced NSCLC, 18 of whom had stage IIIB disease and 12 who had stage IV disease. The median age was 65 years. Patients were treated with a 20-minute infusion of docetaxel, 20 to 40 mg/m²/wk. Radiation therapy was administered 5 d/wk for 5 weeks to a total dose of 60 to 64 Gy using a concomitant boost technique.

Esophagitis, asthenia, and anorexia were the dose-limiting toxicities noted at the docetaxel dose of 40 mg/m². Complete responses were seen in 8 (27%) patients and partial responses in 15 (50%) for an overall response rate of 77%. The recommended phase II dose was 30 mg/m² of docetaxel.

Other Solid Tumors

The Mauer et al Trial

Mauer et al[30] studied different schedules of the combination of docetaxel and concomitant thoracic radiation in 29 patients with NSCLC (20) or esophageal cancer (9). All patients had no prior history of taxane exposure or radiotherapy. Docetaxel was administered either once every 3 weeks (1 dose per cycle); 2 of 3 weeks (2 doses per cycle); or weekly. The total dose of docetaxel per 3-week cycle was escalated from 40 to 75 mg/m². Standard concomitant chest radiotherapy was delivered in 1.8- to 2.0-Gy daily fractions to a total dose of 60 Gy over 6 weeks. The median age of the patients was 64 years and most had a performance status of 0/1.

Dose-limiting esophagitis and neutropenia were encountered in the 1- or 2-dose per cycle schedules at 60 mg/m² per cycle. The maximum tolerated dose for these schedules was 40 mg/m² per cycle. No patients on the weekly schedule developed neutropenia although dose-limiting esophagitis was observed. The maximum tolerated dose for the weekly schedule was 60 mg/m² per cycle or 20 mg/m² weekly. The weekly schedule allowed administration of the the highest total dose of docetaxel with concomitant chest radiotherapy. Of 21 patients who were assessable for response, two achieved a complete response and eight a partial response.

The Koukourakis et al Trial

Koukourakis investigated twice-weekly docetaxel with conventionally fractionated radiotherapy in a phase I trial in 27 patients with lung, brain, and pelvic cancer.[31] The median age of participants was 64 years and included 16 males and 11 females. Among enrolled patients, nine had brain glioblastoma, nine had stage IIIB NSCLC, three had stage IVA cervical cancer, three had endometrial adenocarcinoma, two had bladder carcinoma, and one had an unknown pelvic primary.

Docetaxel was administered twice a week starting at 15 mg/m² and escalated in increments of 4 mg/m² in three-patient cohorts. Radiotherapy consisted of 2 Gy/d, 5 days a week for 6 weeks with a boost to a total of 60 Gy in patients with chest tumors and 64 Gy in those with pelvic tumors. Patients with brain tumors received hyperfractionated radiotherapy (1.4 Gy × 2 fractions per day) to a total dose of 74 Gy.

The maximum tolerated dose of docetaxel for chest and pelvic cancer patients was 15 mg/m² twice a week with radiotherapy. The dose-limiting toxicities were asthenia and mucosal toxicity. In patients with glioblastomas, no toxicity was seen with a docetaxel dose of 23 mg/m² administered twice a week. Encouraging response rates were observed. In patients with NSCLC, three of nine patients achieved a complete response and four of nine a partial response, for an overall response rate of 78%. Among patients with glioblastoma, three had a partial response and four of nine patients with pelvic malignancies had a complete response.

The Tishler et al Trial

Tishler et al[32] studied concurrent docetaxel and radiation therapy in head and neck cancer patients with a poor prognosis. Patients were eligible to enroll if they had received induction chemotherapy with cisplatin(Drug information on cisplatin)/fluorouracil (5-FU)/leucovorin or cisplatin/5-FU and failed to achieve a complete response or had a positive postinduction biopsy. Docetaxel was given at doses of 20, 25, or 30 mg/m² weekly for 6 weeks concurrently with daily radiation, 2 Gy/d to a total dose of 66 to 74 Gy. Twenty-one patients with stage III/IV head and neck cancer were treated, including patients with T3/T4 tumors (16 patients) and N2/N3 disease (11 patients). The dose-limiting toxicities were mucositis, dermatitis, and 2-week treatment interruptions. The maximum tolerated dose of docetaxel was 25 mg/m² weekly.

The overall response rate was 86%, with 12 patients (57%) achieving a complete response and 6 patients (29%), a partial response. At a median follow-up of 35 months, 17 patients were alive, 14 of whom had no evidence of disease. Late toxicities included percutaneous endoscopic gastrostomy in nine patients, tracheostomy in four patients, and esophageal stenosis in one patients.

These phase I trials,[27-32] helped establish the basis for phase II trials, which are discussed below (Table 2).[33-36] Encouraging activity was observed with both in the 3-week and weekly schedules.