Phase 1 study of dose escalation in hypofractionated proton beam therapy for non-small cell lung cancer

Abstract

Background: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control.

Methods and materials: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment.

Results: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT.

Conclusion: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC.

Figure 1

Phase I dose-finding trial monitoring chart.

Figure 2

Distribution of radiation doses to normal structures. Blue bars represent the numbers of patients with doses less than the first cutoff value; red bars, patients with doses between the first and second cutoff values; and the green bars, patients with doses above the second cutoff value. The cutoff values were chosen based on the distribution of doses actually received rather than the dose constraints (see Table 1).

Figure 3

Top, isodose distribution on axial CT slices in the patient who developed a transesophageal fistula. Pink, 52.5 Gy(RBE), dark blue, 45 Gy(RBE), aqua, 40 Gy(RBE), brown, 30 Gy(RBE). Bottom left, dose-volume histogram of normal tissue structures for the same patient. Green, esophagus, dark blue, total lung, pink, heart, aqua, right lung, red, spinal cord. Bottom right, endoscopic image of transesophageal fistula, which had been stented before the patient experienced massive hemoptysis.