Phase II Trial of Intensity-Modulated Photon or Scanning Beam Proton Therapy Both with Simultaneous Integrated Boost Dose Escalation to the Gross Tumor Volume with Concurrent Chemotherapy for Stage II/III Non-Small Cell Lung Cancer - Interim Analysis

Abstract

Multiple studies have shown that high doses, with a biologic effective dose (BED) >100Gy, are required to control tumors in lung tissue. However, delivering high doses is difficult given the location and surrounding tissues at risk such as esophagus, heart and brachial plexus. One way to avoid toxicity is to deliver higher doses to the gross tumor volume (GTV) while keep the PTV dose at standard of 60Gy during the same fraction by using a simultaneous integrated boost (SIB) technique. Intensity modulated photon-based radiation therapy (IMRT) or intensity modulated and energy modulated proton beam therapy (IMPT) techniques allow us to deliver this. We conducted a phase II randomized study to compare IMRT vs. IMPT with concurrent chemotherapy in stage II-IIIB NSCLC patients. Patients with stage II-IIIB NSCLC were randomized to either receiving IMRT or IMPT with an SIB and concurrent chemotherapy. The PTV dose was 60 Gy in 2Gy Relative Biological Effectiveness (RBE) per fraction and the SIB dose was 66-72 Gy (RBE) in 2.2-2.4 Gy (RBE) per fraction. Primary endpoints include assessing and comparing grade III acute toxicity and local progression-free survival (LPFS), calculated from the first day of concurrent chemotherapy. Additionally, we also compared rates of acute toxicity to our prior randomized study data using IMRT and passive scattering proton therapy (PSPT) to 74 Gy in 34 fractions. Statistical analysis included descriptive statistics, Cox regression, and Kaplan-Meier survival. A total of 37 patients received IMRT SIB and 19 patients received IMPT SIB. Grade ≥3 radiation related toxicities (esophagitis, pneumonitis, dermatitis) were observed in 8% (n=3) in IMRT SIB and 0% (n=0) in IMPT SIB patients (p=0.001), which compared favorably with prior randomized trial results of IMRT (any Grade ≥3 toxicity: 21%) vs. PSPT (any Grade ≥3 toxicity: 26%). Specifically, the Grade ≥3 pneumonitis (RP) was 3% and 0% after IMRT SIB and IMPT SIB, respectively (p=0.519). The RP rates compared favorably with our prior trial results, Grade ≥3 RP was 6.5% (p=0.10) and 10.5% (p=0.33) after IMRT and PSPT, respectively. The rates of any Grade ≥3 hematologic toxicities were 8% and 16% after IMRT SIB and IMPT SIB, respectively (p<0.001). This also compared favorably to 79% and 65% after IMRT and PSPT from prior trial data (p<0.001), respectively. Local failure rates at 3 years were 26.5% and 11.1% after IMRT SIB and IMPT SIB, respectively (p=0.472). Median LPFS was 69.77 months for IMRT patients and 67.60 months for IMPT patients (p=0.816). Interim analysis shows that locally advanced NSCLC patients treated in a randomized fashion in this phase II trial had significantly improved acute toxicities compared to our historic data.