Phase I Study of Docetaxel and Concomitant Chest Radiation
Phase I Study of Docetaxel and Concomitant Chest Radiation
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 control.
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 survival.
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 radiotherapy.[7,8]
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 setting.
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 consent.
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 administration schedule.
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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13. Vokes EE, Leopold KA, Herndon II JE, et al: A CALGB randomized phase II study of gemcitabine or paclitaxel or vinorelbine with cisplatin as induction chemotherapy (XRT) in stage IIIB non-small cell lung cancer (NSCLC): Feasibility data (CALGB study #9431) (abstract 1636). Proc Am Soc Clin Oncol 16:455a, 1997.