|
RADIATION THERAPY ONCOLOGY GROUP RTOG 0436 A PHASE III TRIAL EVALUATING THE ADDITION OF CETUXIMAB TO PACLITAXEL, CISPLATIN, AND RADIATION FOR PATIENTS WITH ESOPHAGEAL CANCER WHO ARE TREATED WITHOUT SURGERY
Nonoperative Chemoradiation for Esophageal Cancer: Cisplatin/5-Fluorouracil (5-FU)/Radiation There are 2 conventional treatments for localized esophageal cancer: surgery and non-operative combined chemotherapy plus radiation. Over the past 2 decades, well-designed clinical trials have documented the benefits of combination of chemotherapy and radiation, either as primary therapy or in the neoadjuvant setting. This expanded role has led to a greater understanding of the importance of increased tumor control and simultaneous decrease in normal tissue complications. T he Radiation Therapy Oncology Group completed a phase III randomized trial comparing daily radiation to a total dose of 64 Gy versus concurrent chemotherapy and radiation consisting of 2 cycles of 5-fluorouracil (5-FU), cisplatin and 50 Gy (RTOG 85-01). Patients randomized to receive combination therapy also received two cycles of adjuvant chemotherapy. A total of 129 patients were enrolled between 1986 and 1990. When an interim analysis revealed a difference in outcome that satisfied the early stopping rules, the study was closed. An additional 73 patients who would have been eligible for participation were prospectively registered and treated with combined modality therapy. The median survival was 8.9 months in the radiation-alone group compared with 12.5 months in patients treated with chemotherapy and radiation. The 5-year survival was 26% for those who received combination therapy. None of the patients treated with radiation alone were alive at the time of the final analysis.2,3Given the patterns of failure that were observed in trials such as RTOG 8501, researchers began to investigate ways of improving the local-regional control by intensifying the radiotherapy dose. The potential benefits of external beam radiation dose escalation were evaluated in a phase III intergroup trial (INT 0123). Patients were randomized to concurrent chemotherapy and radiotherapy 50.4 Gy versus the same chemotherapy and 64.8 Gy. The chemotherapy agents (5-FU and cisplatin) were the same in the two studies with only minor differences in the delivery schedule. This study was closed after a planned interim analysis revealed little chance of identifying any significant differences in survival between the 2 groups. The 2-year overall survival between the treatment arms (31% versus 40%) and locoregional failure (56% versus 52%) was not significantly different. The dose of 50.4 Gy remains the standard in current combined modality treatment strategies. In these trials, there was no survival difference among patients with adenocarcinoma and squamous cell cancer. Bimodality Treatment Versus Trimodality Treatment in Esophageal Cancer Multiple concurrent chemoradiation trials have documented 5-year overall survivals in 20% to 25% of treated patients.While there are no direct comparisons in randomized trials, these results are certainly similar to those achieved by surgery alone. Based on broad utilization of concurrent chemoradiation strategies, many researchers recognized the importance of defining the role of surgery within the context of a combined modality treatment approach. Paclitaxel-Based Chemoradiation for Esophageal Cancer Paclitaxel has important single-agent activity in squamous cell and adenocarcinoma of the esophagus and is a radiation sensitizer. There have been multiple phase II studies evaluating paclitaxel-based chemoradiation in esophageal cancer. These trials demonstrated similar complete response rates and survival to cisplatin/5-FU/radiation regimens. Phase II studies from Memorial Sloan Kettering and the Brown University Oncology Group demonstrate substantially less esophagitis (< 5% grade 4 esophagitis) with the regimen of cisplatin, paclitaxel, and radiation without the need for prophylactic enteral feeding tubes. Weekly paclitaxel/cisplatin/radiation regimens do not require central venous catheter devices when paclitaxel is administered by weekly 1-hour infusion compared to continuous-infusion 5-FU–based regimens. Clinical complete responses in sequential phase trials of weekly paclitaxel/cisplatin/radiation and paclitaxel/cisplatin/trastuzumab/radiation have achieved clinical complete responses of 35% to 47% The total dose for both arms will be 50.4 Gy (1.8 Gy/Fx/day) prescribed to the periphery (93% isodose curve) of the PTV. Gross tumor volume (GTV) is defined as all known gross disease as defined by the planning CT and clinical information. Gross tumor includes the primary tumor (GTV-P) only.
A volumetric treatment planning CT study will be required to define GTV and PTV. For this study, the local regional nodes (whether clinically positive or negative) will be included in the clinical target volume (CTV).Each patient will be positioned in an individualized immobilization device in the treatment position on a flat table. Contiguous CT slices, 3-5 mm thickness of the regions harboring gross tumor and grossly enlarged nodes and 8-10 mm thickness of the remaining regions, are to be obtained starting from the level of the cricoid cartilage and extending inferiorly through the liver. The GTV and PTV and normal organs will be outlined on all appropriate CT slices and displayed using beam’s eye view. Normal tissues to be contoured include both lungs, kidneys, skin, heart, spinal cord, esophagus, and liver. A measurement scale for the CT image shall be included. For cervical primaries (defined as tumors above the carina), the bilateral supraclavicular nodes need to be included. The preferable method is a 3-field technique (2 anterior obliques and a posterior field). In most cases, this is not possible; therefore, it is acceptable to initially treat AP/PA to approximately 39.6 Gy, then switch to obliques to exclude the spinal cord. The supraclavicular field, which is excluded from the obliques, can be supplemented with electrons to bring the total dose up to 50.4 Gy (calculated 3 cm below the skin surface). For mid-esophageal primaries (at or below the carina), the paraesophageal nodes need to be included, not the supraclavicular or celiac. For distal/gastroesophageal primaries, the field should include the celiac nodes. Critical Structures (2/13/09) 6.5.1 Normal Tissue Volume and Tolerances: The normal tissues in the table below are to be contoured in their entirety. 6.5.2 The following organs and doses by volume, in the Guidelines on Constraints table below, are guidelines that help determine the risk of developing pneumonitis based on the delivery of the 3D treatment plan. Treating physicians must document the volume of lung receiving > than 20 Gy and attempt to maintain patients in the lowest quartile (as described below) possible. Physicians/dosimetrist should make every effort not to exceed these tolerance levels. All normal tissues assume treatment at 1.8Gy/Fx (uncorrected). There will be no heterogeneity corrections used in the definitions of these doses.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||