NSCLC and Radiation Therapy: Can We Predict Acute Esophagitis?
—Researchers in Michigan recently reported several predictors of esophagitis, a common adverse event during radiation therapy for locally advanced NSCLC. Some of these factors may seem familiar, others may not. Read on to learn the details.
For patients with locally advanced non-small cell lung cancer (NSCLC), esophagitis is a common side effect of radiation therapy, which, if severe enough, can result in a treatment breaks that can compromise treatment efficacy. Prior studies have shown that prolonged radiation treatment time, often due to long or multiple breaks in treatment, is associated with worse overall survival.1,2
“It’s important to understand what contributes to the development of esophagitis in order to better predict which patients are at greatest risk and potentially modify their treatment plan accordingly, to minimize risk and therefore optimize treatment quality,” Daniel Herr, MD, PhD, of the Department of Radiation Oncology, University of Michigan ľֱ School, Ann Arbor, noted in an interview with ľֱ.
While many potential risk factors for esophagitis have been suggested, several radiation dose metrics appear to be significant predictors of esophagitis.3,4 Building off of this knowledge, the investigators behind a new study analyzed data from their state’s oncology network to upgrade predictive models for esophagitis in patients undergoing radiation therapy for locally advanced NSCLC.5
Designing the study and choosing patients
Demographic and clinical data were obtained for patients who received radiation treatment at any of the 27 sites of the Michigan Radiation Oncology Quality Consortium from 2012 to 2022.5 Patients who received definitive radiation therapy for stage II to III NSCLC, whether or not they received concurrent chemotherapy, were included.
Dr. Herr, who is the study’s lead author, says the Consortium uses standardized contouring for critical organs at risk and collects dosimetric data, including the dose received by the esophagus. Outcomes of the current study were risk of grade ≥2 or grade ≥3 esophagitis. Multivariate models were used to analyze associations between outcomes and demographic and clinical characteristics.
The study included 1760 patients. Their median age was 68 years (interquartile range [IQR] 62 to 75), and 958 (54.4%) were male. A total of 279 patients (15.9%) had stage II disease and 1481 (84.2%) had stage III disease. Concurrent chemotherapy was given to 1502 patients (85.3%). Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 in 1283 patients (72.9%) and ≥2 in 444 patients (25.2%).
The median radiation dose was 60 Gy (IQR 60 to 66). The radiation treatment techniques were intensity-modulated radiation therapy for 1393 patients (79.1%), 3D-conformal radiation therapy for 345 (19.6%), and unknown for 22 (1.3%). In 1673 patients (95.1%), the planning target volume was within 2 cm of the esophagus. Four-fifths of patients experienced esophagitis. A total of 552 (31.4%) had grade 1, 813 (46.2%) had grade 2, 38 (2.2%) had grade 3, and 357 (20.3%) had no esophagitis.
Evaluating predictors of esophagitis
Using multivariable analyses, the investigators found the following factors to be associated with increased odds of grade 2 or higher esophagitis:
- Concurrent chemotherapy (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.57 to 3.10; P < .0001)
- ECOG performance status ≥2 compared with 0-1 (OR 1.60, 95% CI 1.24 to 2.06; P= .0003)
- Mean esophageal dose (OR 1.03, 95% CI 1.01 to 1.04; P = .0004)
- Minimum dose of the 2 cc of normal tissue with the highest dose (D2cc) (OR 1.03, 95% CI 1.02 to 1.04; P < .0001)
The investigators also modeled the odds of grade 3 esophagitis after adjusting for D2cc. After adjustment, ECOG performance status ≥2 compared with 0-1 (OR 2.36, 95% CI 1.13 to 4.92; P = .022) and a higher mean esophageal dose (OR 1.05, 95% CI 1.02 to 1.08; P = .002) were associated with grade 3 esophagitis.
Similarly, after adjusting for mean esophageal dose, ECOG performance status ≥2 compared with 0-1 (OR 2.61, 95% CI 1.26 to 5.39; P = .010) and D2cc (OR 1.07, 95% CI 1.03 to 1.12; P = .002) were associated with grade 3 esophagitis. However, concurrent chemotherapy was not associated with grade 3 esophagitis in either model.
Threshold doses and risk
The investigators plotted the mean dose versus D2cc to generate threshold dose curves for a 50% risk of grade 2 esophagitis and a 5% risk of grade 3 esophagitis. This analysis showed that the threshold doses for esophagitis grade 2 or higher were lower for patients undergoing concurrent chemotherapy compared with patients without concurrent chemotherapy, and for patients with ECOG performance status ≥2 compared with patients with ECOG performance status 0-1, regardless of chemotherapy administration. For patients with grade 3 esophagitis, threshold doses were lower in patients with ECOG performance status ≥2 compared with patients with ECOG performance status 0-1.
For all patients, regardless of ECOG performance status or chemotherapy status, a mean esophageal dose of 22 Gy or D2cc dose of 50 Gy corresponded to a 50% risk for esophagitis grade 2 or higher. For a 3% risk for grade 3 esophagitis, the mean esophageal dose was 29 Gy, and the D2cc dose was 61 Gy.
Developing useful benchmarks
Dr. Herr told ľֱ that while clinicians already understand that concurrent chemotherapy and higher radiation doses increase the risk of esophagitis, they may not have considered the impact of performance status.
“Patients who are unable to function optimally in their daily life—in medical parlance, this would be those with poor performance status—really appear to be at greater risk of acute esophagitis during treatment,” Dr. Herr says. “Performance status isn’t something that one might routinely think of as affecting toxicity, but in our data, it really matters.”
Limitations of the study include its reliance on clinician-reported outcomes only, variability in treating physicians’ contouring practices, and the lack of information about specific chemotherapy regimens.
The investigators hope their results can provide useful information for clinicians treating patients with NSCLC. “We also produced easy-to-reference curves for the likelihood of toxicity at different doses to the esophagus, accounting for performance status and receipt of chemotherapy,” Dr. Herr says. “I think these provide benchmarks that can be used to optimize treatment planning for individual patients.”
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