SBRT Dose Escalation for Reirradiation of Inoperable Lung Lesions

Study Overview
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Brief Summary
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Prospective phase I study to evaluate the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation. Dose limiting toxicity will be pneumonitis ≥ G3. The potential advantage of the dose escalation planned in this study is the delivery of an ablative dose to radically treat patients with inoperable local relapse, without unacceptable toxicity.

Detailed Description
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Radical dose radiotherapy (RT) is frequently used in thoracic malignancies, both for early stage primary non-small cell lung cancer (NSCLC) and for secondary lesions from other primary tumors, particularly in the setting of oligometastatic patients. Although development of distant metastases is the predominant pattern of failure after treatment with radical RT, isolated local recurrences, defined as a tumor recurrence overlapping the 50% isodose field, are still observed and are becoming more and more frequent along with the prolongation of life expectancy in cancer patients. Salvage options for isolated post-radiation local failures are limited, with surgery or retreatment with radiotherapy as potential modalities. While salvage surgical resection after previous thoracic irradiation has shown encouraging results, most patients experiencing post-radiation local relapse are not surgical candidates. Therefore, reirradiation may be the only viable salvage option for many patients. Retreatment with CFRT has been reported for locoregional failures, with generally-poor outcomes. Although, salvage SBRT after initial CFRT has been described in select small series of heterogeneous patient groups ranging from early stage to locally-advanced and metastatic, few data exist to guide us on the role of reirradiation with SBRT for isolated recurrences after initial SBRT for early-stage NSCLC. Due to the heterogeneity and the low numerosity of these experiences, important questions regarding the safety and efficacy in this setting are still largely unanswered. Particularly, the possibility of delivering a second course of ablative dose RT (BED ≥ 100 Gy) is almost unexplored. Based on this background, we designed a prospective phase I study to evaluate the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation. Dose limiting toxicity will be pneumonitis ≥ G3. The potential advantage of the dose escalation planned in this study is the delivery of an ablative dose to radically treat patients with inoperable local relapse, without unacceptable toxicity.

Official Title
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Phase I Trial Evaluating Stereotactic Body Radiotherapy (SBRT) Dose Escalation for Reirradiation of Inoperable Lung Lesions

Conditions
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Non Small Cell Lung Cancer, Lung Metastases

Intervention / Treatment
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* Radiation: SBRT dose escalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inoperable primary non-small cell lung cancer or other metastatic primaries with lung metastases, already treated with radical dose RT; Peripheral lesion (> 2 cm from trachea-bronchial tree); Inoperable local recurrence (defined as a tumor recurrence overlapping the 50% isodose field) confirmed by documented radiographic findings and/or pathological biopsies within the thoracic area; Patients had previously received curative intent RT of more than 50 Gy for conventionally fractionated RT or a biologically equivalent dose of more than 75 Gy for SBRT; No active distant metastasis or controlled distant metastasis at the time of re-irradiation Exclusion Criteria: Central or ultra-central lesion(s); Incapability of understanding and signing informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study is designed to determine the Maximum Tolerated Dose (MTD) that could be safely delivered in the lung reirradiation setting. The MTD was defined as the highest dose level in which a proportion of 1 out of 5 or fewer patients experienced DLT. Due to the late onset nature of DLT, in order to allow for continuous accrual without sacrificing patient safety or the accuracy of identifying the MTD, the Time-To-Event Bayesian Optimal Interval (TITE-BOIN) design will be used.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT Level 1<br>The starting dose level will be SBRT 30 Gy in 5 fractions (level 1 or L1). | Radiation: SBRT dose escalation<br>* Re-Stereotactic Body Radiation Therapy (SBRT) with increasing dose levels, from 30 Gy in 5 fractions to 50 Gy in 5 fractions.<br>|
| Experimental: SBRT Level 2<br>If the starting dose is tolerated in the first 5 patients, the next dose will be SBRT 40 Gy in 5 fractions (level 2 or L2) | Radiation: SBRT dose escalation<br>* Re-Stereotactic Body Radiation Therapy (SBRT) with increasing dose levels, from 30 Gy in 5 fractions to 50 Gy in 5 fractions.<br>|
| Experimental: SBRT Level 3<br>If the second dose is tolerated in the next 5 patients, the next dose will be SBRT 50 Gy in 5 fractions (level 3 or L3) | Radiation: SBRT dose escalation<br>* Re-Stereotactic Body Radiation Therapy (SBRT) with increasing dose levels, from 30 Gy in 5 fractions to 50 Gy in 5 fractions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | maximal tolerated dose (MTD) of SBRT for thoracic re-irradiation | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other toxicities | To evaluate acute and late toxicities other than dose limiting toxicity | 5 years | 
| Overall survival | To evaluate overall survival of patients undergoing thoracic re-irradiation. | 5 years | 
| Local control | To evaluate local control of patients undergoing thoracic re-irradiation. | 5 years | 
| PFS | To evaluate progression free survival of patients undergoing thoracic re-irradiation. | 5 years |