Date of Award

January 2024

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Henry Park

Abstract

Hypofractionated radiation therapy (HFRT) is emerging as a preferred treatment for lung cancer patients ineligible for stereotactic body radiotherapy (SBRT). Normally, a standard-dose (SD-HFRT) hypofractionation regimen administers 60 Gy across 15 fractions, equating to a biologically effective dose (BED10) of 84.0, which is less than that of ablative SBRT. The first part of this thesis contrasts the clinical outcomes of patients receiving a high-dose (HD-HFRT) protocol, delivering 72 Gy in 18 fractions with a BED10 of 100.8, against those on SD-HFRT. Our research examines whether HD-HFRT enhances local control (LC) and overall survival (OS) rates while maintaining comparable rates of grade 3+ toxicity to SD-HFRT.

Furthermore, the scarcity of data concerning dose-volume predictors for radiation pneumonitis and esophagitis under HFRT is notable, particularly given that existing guidelines predominantly reference conventional fractionation. This investigation seeks to pinpoint dosimetric risk factors tied to radiation pneumonitis in patients undergoing HFRT at 4 Gy per fraction. Key variables of interest include lung V20, mean lung dose (MLD), and lung V5, as potential indicators of grade ≥2 pneumonitis. Concurrently, our research evaluates the predictive capacity of esophageal V20, mean esophageal dose (MED), and esophageal V5 in forecasting the onset of grade ≥2 esophagitis.

A retrospective database was created of all patients at our institution who received either thoracic SD-HFRT or HD-HFRT between 2013 and 2020. Data collection was done manually. Baseline variables were compared by chi-square analysis and logistic regression. We analyzed the association between treatment regimens with LC and OS (log-rank test and Cox proportional hazards regression), as well as grade 3+ toxicity. Data analysis was performed utilizing STATA.

To summarize, our study has 3 primary aims:

Aim 1: Compare the Two HFRT Regimens A total of 107 patients were included, among whom 55 (51.4%) received SD-HFRT and 52 (48.6%) received HD-HFRT. Median age was 73, 88.8% of patients had non-small cell lung cancer, 81.3% received lung-only treatment, and 52.3% had an ultra-central tumor location defined as abutting or within 1 cm of critical structures with 45.8% directly abutting one of these structures. Patients with HD-HFRT were more likely to have lung-only treatment (92.3% vs. 70.9%, p=0.005) and stage I disease (46.2% vs 23.6%, p=0.01) than those with SD-HFRT, but had a similar proportion of ultra-central tumors (57.1% vs. 54.9%, p=0.82). Among those with ultra-central tumors, patients with HD-HFRT had statistically significantly higher LC (2-year 86.6% vs 71.2%, 3-year 86.6% vs 42.2%, HR 0.26 [95% CI 0.08-0.84] p=0.02) and a non-statistically significant trend towards higher OS (2-year 63.8% vs 40.0%, 3-year 46.2% vs 31.1% HR 0.55 [95% CI 0.28-1.09] p=0.09) compared to those with SD-HFRT.

Aim 2: Identify Dose-Volume Predictors of Grade 2+ Radiation PneumonitisOver a median 24.3-month follow-up, 18 patients (16.8%) developed grade ≥2 radiation pneumonitis, with no significant difference between the two dose regimens (17.3% vs. 16.3%, p=0.88). Four patients (3.7%) experienced grade ≥3 pneumonitis, including two grade 5 cases. Patients with grade ≥2 pneumonitis had significantly higher lung V20 (mean 23.4% vs. 14.5%, p<0.001), MLD (mean 13.0 Gy vs. 9.5 Gy, p<0.001), and lung V5 (mean 49.6% vs. 40.6%, p=0.01). Dose thresholds for a 20% risk of grade ≥2 pneumonitis were lung V20 <17.7%, MLD <10.6 Gy, and V5 <41.3%.

Aim 3: Identify Dose-Volume Predictors of Grade 2+ EsophagitisTumors within 2 cm of the esophagus comprised 27.1% of total patients, and tumors within 1 cm of the esophagus comprised 10.3% of total patients. Median follow-up was 24.3 months. There were 13 cases (12.1%) of grade ≥2 esophagitis, with no statistically significant difference between 60 Gy and 72 Gy (9.4% vs. 14.8%, p=0.39). Three patients (2.8%) developed grade 3 esophagitis, with no cases of grade 4-5 esophagitis. When comparing patients who experienced a grade ≥2 esophagitis vs. those who did not, there was a statistically significant difference in esophagus Dmean (mean 13.8 Gy vs. 9.7 Gy, OR 1.11 [95% CI 1.01-1.23], p=0.02), esophagus Dmax (mean 45.8 Gy vs. 35.9 Gy, OR 1.05 [95% CI 1.00-1.09], p=0.03), and esophagus V40 (mean 5.5% vs. 2.3%, OR 1.10 [95% CI 1.01-1.21], p=0.04), but no statistically significant difference in esophagus V60 (mean 0.20% vs. 0.01%, OR 7.65 [95% CI 0.23-255.8], p=0.26).

As HFRT becomes increasingly common for treatment of cancer across all disease sites (and in thoracic tumors especially), it is critical that the presentation and identification of patients that would benefit from these regimens is standardized and constraints found to mitigate their risk of side effects that can significantly affect their quality of life.

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