There is an intermediate stage during the natural history of many solid
tumors during which patients have locally or regionally advanced disease
without clinically overt, systemic metastasis. Traditional treatment
for these patients consisted of surgery and/or radiotherapy; however, only
a small percentage of patients were cured, and treatment failures due to
inadequate locoregional or systemic control of the disease occurred in
a high percentage of patients.
Therefore, patients with intermediate-stage solid tumors require more
effective locoregional therapy, as well as the administration of systemic
therapy to eradicate microscopic metastases. These observations have led
to the widespread investigation of multimodality therapies, including induction
(neoadjuvant) chemotherapy and concomitant chemoradiotherapy.
Among the common malignancies in the chest, non-small-cell lung cancer
frequently is diagnosed in an intermediate stage (stages IIIA and IIIB).
The majority of these patients develop systemic disease outside the ipsilateral
side of the chest, and a significant proportion fail to achieve locoregional
The administration of induction chemotherapy utilizing cisplatin (Platinol)
and vinblastine for two cycles has been demonstrated in two studies to
result in a significant increase in median and long-term survival, as compared
with radiotherapy alone.[3,4] Another study investigating induction chemotherapy
has suggested that improved survival occurs as a function of decreased
systemic recurrence rate. Locoregional control, on the other hand, does
not appear to be increased through the use of induction chemotherapy.
Randomized studies investigating concomitant chemoradiotherapy vs radiotherapy
alone have frequently focused on cisplatin administered as a single agent.
Daily, weekly, and monthly administration of the drug during radiotherapy
have been investigated. To date, only one study has shown an increase
In this study, improved survival occurred as a function of an increase
in locoregional control. These data suggest that increasing locoregional
control may translate into a survival benefit for some patients with intermediate
non-small-cell lung cancer and that concomitant chemoradiotherapy may be
one tool to achieve that goal. This is further substantiated by recent
reports indicating increased survival in patients treated with hyperfractionated
radiation therapy schedules or the regimen of continuous hyperfractionated
accelerated radiation therapy (CHART), as opposed to single daily-fraction
Similar observations supporting the use of combined-modality therapy
have been made in esophageal cancer. Results from two studies investigating
the use of cisplatin and fluorouracil (5-FU) with concomitant radiotherapy
demonstrated an increase in survival in patients with unresectable disease
or resectable adenocarcinoma.[9,10] In addition, an increase in locoregional
and systemic tumor control was reported.
In recent years, several new chemotherapeutic agents with activity in
non-small-cell lung cancer and/or esophageal cancer have been identified,
including the taxanes docetaxel (Taxotere) and paclitaxel (Taxol). In
the preclinical setting, the taxanes appear to be potent radiation enhancers
by inducing cell-cycle arrest in the G2/M-phase.[11,12] Studies
have shown that cells in the G2/M-phase are more sensitive to
radiation than cells in other phases of the cell cycle.
In addition, concurrent administration of chemotherapy and radiation
has resulted in promising data in intermediate-stage chest malignancies.
Thus, the investigation of new chemotherapeutic compounds with concomitant
radiation therapy is a high priority.
Because the clinical interactions of docetaxel and concomitant chest
radiotherapy had not been described previously, we initiated a phase I
study to define the maximum tolerated dose and dose-limiting toxicities
of docetaxel when administered with concomitant chest radiation. In addition,
we investigated the administration of docetaxel on a variety of schedules
to determine the most feasible schedule of administration in a clinical
Patients and Methods
This ongoing study began in 1994 at the University of Chicago, and patient
enrollment continues. Criteria for study participation includes patients
with histologically or cytologically confirmed advanced solid tumors and
those who require chest radiotherapy as a component of their overall treatment
plan. Also eligible are patients with metastatic or local/regionally advanced
disease in the chest, as well as those requiring adjuvant radiation therapy
following surgical resection of an advanced intrathoracic malignancy.
Further eligibility criteria include a Cancer and Leukemia Group B status
of 0 to 2, normal bone marrow, and normal hepatic and renal function. Although
patients are not to have received hormonal or chemotherapy within 4 weeks
of study initiation, prior radiation therapy to less than 25% of the active
bone marrow is allowed.
Patients with known brain metastases or meningeal involvement are excluded.
In addition, patients with symptomatic peripheral neuropathy (more than
grade 1) or serious additional medical disease are excluded. Similarly,
prior therapy with a taxane is not allowed. All patients signed an informed
Pretreatment staging procedures include routine physical examination
and hematologic and serum chemistry blood tests.
The dose-escalation schedule is shown in Table
1. The overall goals of this study are to determine the optimal schedule
and maximum tolerated dose of docetaxel. Radiation therapy is administered
at 180 to 200 Gy/fraction, administered Monday through Friday for each
of 5 to 6 consecutive weeks. The total planned radiation dose is 50 to
60 Gy. The docetaxel dose has been escalated from 40 to 60 to 75 mg/m²
per 3-week cycle (administered twice during a 6-week course of radiotherapy).
Beginning 24 hours prior to each dose of docetaxel, oral dexamethasone
is administered at 8 mg twice daily for a total of 6 doses.
A minimum of three evaluable patients are entered at each dose level.
There is no dose escalation in individual patients. The maximum tolerated
dose is defined as the dose at which less than 33% of patients experience
dose-limiting toxicity. Grade 3 or 4 nonhematologic toxicity (excluding
nausea, vomiting, anemia, and alopecia) and grade 4 neutropenia exceeding
4 days' duration or complicated by a neutropenic fever or grade 4 thrombocytopenia
represent dose-limiting toxicities.
This study investigating docetaxel as a single agent with concomitant
radiotherapy to the chest opened in 1994. To date, 29 patients have been
enrolled, including 19 men and 10 women (Table
2). Of the 29 patients, 20 had non-small-cell lung cancer and 9 had
esophageal cancer. Only 1 patient has received prior chemotherapy; 7 patients
have undergone previous surgery. The study data are currently undergoing
final analysis regarding the recommended phase II doses and the optimal
This phase I study of docetaxel with concomitant radiotherapy is designed
to define the optimal dose and schedule of docetaxel with standard chest
radiotherapy. Following completion of the study, the integration of this
regimen into a curative-intent treatment approach for intermediate-stage
malignancies of the chest should be pursued.
Regarding non-small-cell lung cancer, induction chemotherapy results
in increased median and long-term survival rates. Similarly, increased
tumor control within the chest may be of benefit to the patient. Therefore,
it would appear to be of interest to investigate docetaxel-based induction
chemotherapy to be followed by docetaxel with concomitant chest radiotherapy.
In particular, two to three cycles of docetaxel with cisplatin or carboplatin
(Paraplatin), followed by docetaxel with radiotherapy, may be of interest.
The Cancer and Leukemia Group B is currently pursuing this sequencing strategy,
utilizing several of the new chemotherapeutic agents.
In this randomized phase II study, patients receive two cycles of a
new chemotherapeutic agent, plus cisplatin as induction chemotherapy, followed
by two additional cycles of the same chemotherapy regimen with concomitant
standard chest radiotherapy. Patients are randomized to receive either
paclitaxel, vinorelbine (Navelbine), or gemcitabine (Gemzar) with the cisplatin
dose. A similar study design utilizing docetaxel would be of great interest,
given the higher efficacy reported in cisplatin-resistant patients with
advanced non-small-cell lung cancer.
At the same time, integration of concomitant docetaxel with radiotherapy
into the management of patients with esophageal cancer is currently being
examined in a phase II multicenter study. Patient enrollment is ongoing.
Eligible patients with advanced but nonmetastatic esophageal cancer receive
three cycles of cisplatin/docetaxel followed by docetaxel with concomitant
chest radiotherapy. Patients with resectable disease undergo esophagectomy
following the completion of radiotherapy, and patients with unresectable
disease complete concomitant chemoradiotherapy with a boost dose of radiation.
Preliminary results are expected in the near future.
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