Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non

Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non–small-cell lung cancer

Steven E. Schild, M.D. collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic IJROBP 2006;65:1106

Purpose: This trial was performed to determine the maximum tolerated dose (MTD) of radiation that can be administered with carboplatin and paclitaxel.

Methods and Materials: This trial included 15 patients with unresectable non–small-cell lung cancer. Paclitaxel (50 mg/m2) and carboplatin (area under the curve = 2) were given weekly during radiation therapy (RT). The RT included 2 Gy daily to an initial dose of 70 Gy, and the dose was increased in 4 Gy increments until determining the MTD. The MTD was defined as the highest safely tolerated dose where at most 1 patient of 6 experienced dose-limiting toxicity (DLT) with the next higher dose having at least 2 of 6 patients experiencing DLT. Three-dimensional treatment planning techniques were used without prophylactic nodal RT.

Results: Two patients were not evaluable because they did not receive therapy according to the protocol. No DLTs occurred in the 3 patients who received 70 Gy, 1 DLT occurred in the 6 patients who received 74 Gy, and 2 DLTs occurred in the 4 patients who received 78 Gy. The DLTs included Grade 3 pneumonitis (n = 2) and Grade 4 pneumonitis (n = 1). There have been 3 deaths during follow-up ranging from 14 to 38 months (median, 28 months).

Conclusions: The MTD of the RT was 74 Gy with weekly carboplatin and paclitaxel. The Phase II portion of this trial is currently under way. The goal is to improve local control and survival with higher doses of RT delivered with this combined modality approach.

Patients eligible for this trial included those with medically or surgically unresectable histologically verified NSCLC, Eastern Cooperative Oncology Group performance status of 0–1, weight loss <10% in the prior 3 months, no prior therapy for this malignancy, and adequate laboratory and pulmonary functions. Adequate laboratory function included an absolute neutrophil count >1500/mL, platelet count >100,000/mL, total bilirubin level <1.5× the upper limit of normal, aspartate transaminase <3× the upper limit of normal, and a creatinine clearance ?40 mL/min. Adequate pulmonary function was defined as a forced expiratory volume in 1 s of >1 L. Staging studies included history, physical examination, chest X-ray, computed tomography (CT) of the chest, complete blood cell count, and chemistry panel.

Treatment included weekly intravenous paclitaxel (50 mg/m2) and carboplatin (AUC = 2) during RT. This was chosen based on a Phase II trial performed by Choy et al, which included weekly paclitaxel (50 mg/m2), carboplatin (area under the curve [AUC] = 2), and concurrent RT (66 Gy/33 fractions) (14). After the RT, patients received two more cycles of the same chemotherapy. Median survival was quite favorable at 20.5 months. The current study incorporated the chemotherapy used by Choy et al. during the RT. However, the patients in the current study did not receive further chemotherapy after the RT was completed.

The RT included the delivery of 2 Gy once a day, 5 days per week, to an initial dose of 70 Gy (dose level 1). The total dose was increased in 4 Gy increments until the MTD was determined. The clinical target volume (CTV) included the primary tumor plus adenopathy based on CT. Adenopathy was defined as any lymph node present on the CT of the chest that was greater than 1 cm in short diameter. The planning target volume (PTV) included the CTV plus respiratory motion. The RT fields included a 1.5-cm margin between the PTV and the block edge to ensure adequate coverage of gross disease. No prophylactic nodal RT was administered. RT was delivered with multiple fields using 3D treatment planning. The dose was prescribed to an isodose curve that encompassed at least 95% of the PTV. No more than 20% of the PTV could receive >110% of its prescribed dose. In addition, no more than 1% of the PTV could receive <93% of its prescribed dose. No more than 1% or 1 cc of the tissue outside the PTV could receive >110% of the prescription dose. Treatment was delivered with 6- to 10-MV X-rays. No tissue inhomogeneity corrections were used.

The following dose–volume limitations were mandated. No part of the spinal cord could receive greater than 48 Gy. No more than 40% of the total lung volume could receive 20 Gy. The full circumference of the esophagus could not receive 60 Gy. The entire brachial plexus could not receive 60 Gy. One-third of the heart could not receive 60 Gy, two-thirds could not receive 50 Gy, and the entire heart could not receive 40 Gy. Every effort was made to avoid the overlap of all treatment fields on any portion of the skin and subcutaneous tissues. This was done to prevent delivering the total prescribed dose to a section of the skin or subcutaneous tissues.

There were a total of 3 DLTs observed, Grade 3 pneumonitis (n = 2) and 1 Grade 4 pneumonitis. Grade 3 pneumonitis referred to treatment-related lung symptoms severe enough to require supplemental oxygen. Grade 4 pneumonitis required the use of a respirator for more severe symptoms. The percent of total lung volume receiving 20 Gy (V20) for the entire cohort ranged from 9% to 37% (median, 24%). Those with Grade 3+ pneumonitis did not have significantly higher V20 values than those without severe pneumonitis, with V20 values that ranged from 10% to 26% (median, 24%) compared with 9% to 37% (median, 25%) for those without Grade 3+ pneumonitis (p = 0.57, Wilcoxon signed rank test).