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Docetaxel and Radiation as Combined-Modality Therapy

Docetaxel and Radiation as Combined-Modality Therapy

ABSTRACT: Combined-modality approaches for the treatment of non-small-cell lung cancer (NSCLC), head and neck cancer, and esophageal cancer offer survival benefits by improving locoregional control and treating micrometastatic disease. The taxanes are active, tolerable drugs in these solid tumors and have radiation-sensitizing activity. Docetaxel (Taxotere) has been studied in combination with radiation with favorable results. In phase II trials, docetaxel combined with radiation therapy resulted in response rates of up to 80%, with the most commonly used schedule being docetaxel at 20 to 30 mg/m² per week with concomitant radiation administered at fractions of 1.8 to 2.0 Gy, 5 days a week over 5 to 6 weeks. Studies of docetaxel and platinum combinations have been conducted predominantly in patients with NSCLC. Early results show good activity and acceptable toxicity, with esophagitis or mucositis being dose-limiting. Doses of docetaxel at 20 mg/m² per week combined with cisplatin at 25 mg/m² or carboplatin (Paraplatin) at an area under the concentration-time curve (AUC) of 2 with concomitant radiation appear to be well tolerated and active. Future investigations, including phase III trials in patients with locally advanced NSCLC, are encouraged. Current trials are studying various design schedules, including induction chemotherapy with radiation followed by consolidation chemotherapy. [ONCOLOGY 16(Suppl 6):97-105, 2002]

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 (Gemzar).[2-5] The taxanes, in
particular, are active, tolerable drugs for the treatment of solid tumors, and
they possess radiation-sensitizing activity. 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 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/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.

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