Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer

Abstract

Purpose This randomized trial compared outcomes of passive scattering proton therapy (PSPT) versus intensity-modulated (photon) radiotherapy (IMRT), both with concurrent chemotherapy, for inoperable non-small-cell lung cancer (NSCLC). We hypothesized that PSPT exposes less lung tissue to radiation than IMRT and thereby reduces toxicity without compromising tumor control. The primary end points were grade ≥ 3 radiation pneumonitis (RP) and local failure (LF). Patients and Methods Eligible patients had stage IIB to IIIB NSCLC (or stage IV NSCLC with a single brain metastasis or recurrent lung or mediastinal disease after surgery) who were candidates for concurrent chemoradiation therapy. Pairs of treatment plans for IMRT and PSPT were created for each patient. Patients were eligible for random assignment only if both plans satisfied the same prespecified dose-volume constraints for at-risk organs at the same tumor dose. Results Compared with IMRT (n = 92), PSPT (n = 57) exposed less lung tissue to doses of 5 to 10 Gy(RBE), which is the absorbed Gy dose multiplied by the relative biologic effectiveness (RBE) factor for protons; exposed more lung tissue to ≥ 20 Gy(RBE), but exposed less heart tissue at all dose levels between 5 and 80 Gy(RBE). The grade ≥ 3 RP rate for all patients was 8.1% (IMRT, 6.5%; PSPT, 10.5%); corresponding LF rates were 10.7% (all), 10.9% (IMRT), and 10.5% (PSPT). The posterior probability of IMRT being better than PSPT was 0.54. Exploratory analysis showed that the RP and LF rates at 12 months for patients enrolled before versus after the trial midpoint were 21.1% (before) versus 18.2% (after) for the IMRT group (P = .047) and 31.0% (before) versus 13.1% (after) for the PSPT group (P = .027). Conclusion PSPT did not improve dose-volume indices for lung but did for heart. No benefit was noted in RP or LF after PSPT. Improvements in both end points were observed over the course of the trial.

Trial registration: ClinicalTrials.gov NCT00915005.

Fig 1.

(A) The adaptive randomization process. Eligibility criteria included stage II to IIIB non–small-cell lung cancer (NSCLC), or stage IV NSCLC with a single brain metastasis or isolated tumor recurrence after surgical resection; 50% of patients had disease progression after systemic chemotherapy before enrollment. All patients underwent four-dimensional computed tomography (4D CT)–based treatment simulation; target volume contours and preliminary plans were reviewed before patients were randomly assigned. The prescribed dose for both sets of treatment plans (intensity-modulated [photon] radiation therapy [IMRT] and passive scattering proton therapy [PSPT]) was 74 Gy (relative biologic effectiveness [RBE]). If one of the two plans did not meet prespecified dose constraints (Data Supplement), the prescribed dose was reduced to 66 Gy for a second pair of plans. Patients were randomly assigned only when both IMRT and PSPT plans met dose constraint standards. If one of the two plans did not meet dose constraints at 66 Gy(RBE), the patient was treated with the modality that produced the acceptable dose distribution. During treatment, weekly 4D CT scans were obtained for all patients and additional treatment plans were created as needed to account for anatomic changes. Patients were contacted weekly with a questionnaire to assess symptoms of pneumonitis to ensure that radiation pneumonitis events (toxicity assessment) were accurately noted. (B) Cumulative patient random assignment and enrollment over time. The inset shows posterior randomization probability to IMRT, with the vertical dashed line representing the last date (June 22, 2010) at which the randomization probability was 0.5. The first patient was randomly assigned on August 17, 2009, and the last patient was assigned on April 18, 2014; 60% to 67% of all patients who consented to participate were eligible for random assignment. (C) Trial profile. The final numbers of patients included in the analysis are shown in boldface. GTV, gross tumor volume; Gy(RBE), the absorbed radiation dose, in Gy, multiplied by the relative biologic effectiveness factor (RBE) for protons; MDSAI, MD Anderson Symptom Inventory.

Fig 2.

(A) Box plot of mean radiation doses to the lung, esophagus, and heart. Mean doses to the lung and esophagus were no different between the two treatment groups (intensity-modulated [photon] radiation therapy [IMRT] and passive scattering proton therapy [PSPT]), but the mean heart dose was lower for those treated with protons (P = .002). Whiskers indicate 1.5 times the interquartile range above and below the mean; dots represent outliers. (B) Box plot of distributions of dose-volume indices for the lung and heart. PSPT led to smaller volumes of lung being exposed to low volume doses (V_5-10) and larger volumes of lung exposed to ≥ 20 Gy (relative biologic effectiveness [RBE]). PSPT reduced the volume of heart exposed to all dose levels measured (5 to 80 Gy [RBE]). Whiskers indicate 1.5 times the interquartile range above and below the mean; dots represent outliers.

Fig 3.

Cumulative incidence of severe (grade 3) radiation pneumonitis (RP) and local failure (LF) according to treatment among patients who were randomly assigned and treated according to random assignment. (A) Cumulative incidence of RP and LF for patients treated with intensity-modulated (photon) radiation therapy (IMRT) or passive scattering proton therapy (PSPT). (B) Cumulative incidence of RP. (C) Cumulative incidence of LF. Results were similar when patients were analyzed by intention to treat or by treatment received (data not shown).

Fig 4.

(A) Cumulative incidence of radiation pneumonitis (RP) and local failure (LF) among patients who were randomly assigned and treated according to time of enrollment (early indicates enrollment before the midpoint of the trial [September 27, 2011; median follow-up, 29 months]; later indicates enrollment after the midpoint [median follow-up, 23 months]). Patients in the later group had lower rates of RP and LF. Similar results were found when patients were analyzed by intention to treat or by treatment received (data not shown). (B) Cumulative incidence of RP among patients who were randomly assigned and treated according to time of enrollment. In the intensity-modulated (photon) therapy (IMRT) group, RP occurred in both the early and the later groups; in the passive scattering proton therapy (PSPT) group, RP occurred only in the early group. The results suggest the existence of a learning curve for the delivery of PSPT, with corresponding improvements in PSPT over the course of the trial.