Clinical Investigation
Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer

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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.

Introduction

Non-small cell lung cancer (NSCLC) is frequently diagnosed in patients of an advanced age who are likely to have additional comorbid conditions and poor performance status, making them unable to tolerate standard chemoradiation therapy 1, 2, 3. Effective regimens that omit concurrent systemic therapy are needed for such patients. In addition, if shorter radiation courses could be delivered for locally advanced disease, patients who could tolerate it could receive systemic doses of sequential chemotherapy sooner than would otherwise be possible, which could reduce the risk of distant metastases and increase the cost effectiveness of radiation by reducing the number of fractions to be given.

Numerous studies have been published regarding hypofractionated stereotactic radiation therapy for early-stage lung cancer (4), but analyses of hypofractionated regimens for locally advanced disease are limited. One institution reported 2 studies in which 45 Gy in 3-Gy fractions was given to patients with poor performance status and noted that rates of response and locoregional control were comparable despite poor prognostic factors 5, 6. The advent of increasingly conformal techniques may allow further dose escalation to improve the likelihood of local control while sparing surrounding normal structures.

To address this possibility, we undertook this prospective phase I study to assess the safety of dose-escalating hypofractionated proton therapy, given without chemotherapy, for NSCLC. Our hypothesis was that the favorable dose-distribution characteristics of proton beam therapy (PBT) would render doses of up to 60 Gy(RBE) (biologically equivalent dose [BED] 84 Gy) feasible even for patients with poor performance status.

Section snippets

Patients

This study was approved by the appropriate institutional review board. Eligibility criteria included histologically or cytologically documented NSCLC. Multiple histologies were initially allowed because of the phase 1 nature of the study, but to maintain uniformity, only the results with NSCLC are included in this report. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents such as epidermal growth factor receptor (EGFR) or vascular endothelial growth factor

Results

Twenty-five patients with NSCLC were enrolled in this trial. Patient characteristics are shown in Table 2. Sixty-four percent of patients had mediastinal involvement, including those who did not have NSCLC. Patients without mediastinal involvement were included in this study if their tumors were thought to be too large (typically >4 cm) or too centralized (ie, adjacent to the mediastinum or bronchial tree) to be treated with stereotactic ablative body radiation. No DLT was experienced during

Discussion

Pertinent findings from this phase 1 dose-escalation study of an intermediate hypofractionated regimen for NSCLC were as follows. First, the modified dose constraints used were effective, both in allowing treatment of patients with extensive mediastinal disease and in limiting the rate of high-grade acute toxicity. Second, hypofractionated regimens up to 60 Gy(RBE) in 15 fractions were tolerated well in most cases, even when patients were not candidates for systemic therapy because of poor

Acknowledgment

The authors thank Christine Wogan, MS, ELS, for reviewing and editing the manuscript of this article.

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Supported in part by NCI Cancer Center Support (core) Grant CA16672 and P01 CA021239.

Conflict of interest: none.

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