Less pneumonia after nCRT and resection in oesophageal cancer using proton RT

Purpose/Objective
Current treatment in oesophageal cancer (EC) consists of neoadjuvant chemoradiotherapy (nCRT) followed by a surgical resection. This treatment is accompanied by serious complications risk, of which pneumonia is one of the most frequently observed complications. This is partly a result of the mean dose to the lungs, which is directly linked to the incidence of pulmonary complications3. Photon-based radiotherapy (PhRT) has long been the conventional treatment approach. However, proton radiotherapy (PRT) has emerged as a promising alternative since reductions in radiation dose to healthy tissues can be obtained4,5. A RCT showed that the dose reduction achieved by PRT significantly reduced the risk of developing adverse events, including pneumonia and re-intubation6.
The aim of the current analysis is to test the hypothesis that PRT can effectively reduce the occurrence of pneumonia among patients undergoing multimodal treatment for oesophageal cancer.
Material/Methods
At our department curative EC patients are enrolled in a prospective data registry. For the current analysis, we selected patients who underwent nCRT between October 2014 and June 2022 followed by a surgical resection. We excluded patients with a history of thoracic radiotherapy/resection and those diagnosed with neuroendocrine carcinoma. Since April 2020, EC patients can be selected for PRT using the model-based approach.
In this study, a complete case association analysis was performed to analyse the impact of patient, treatment and tumour characteristics on the risk of pneumonia. Pneumonia was defined as CTCAE grade 2 or higher within 6 months after the end of nCRT. Differences in baseline characteristics between the PRT and PhRT groups were identified with a Chi-Square-test or the Mann-Witney-U test. Radiation doses at intervals of 5 Gy (V5,..., V40) of the heart and lungs were calculated to analyse the effect of the DVH parameters. To cope with the multicollinearity of the DVH parameters, a PCA analysis was performed. A univariable logistic regression analysis was performed to identify relevant parameters (p<0.2). To evaluate potential confounding, possible confounders were introduced into the univariable model of the significant variables (10% coefficient chance). Subsequently, variables that possibly interact, based on clinical knowledge, were multiplied within a logistic regression model to assess potential interactions (p<0.1). Finally, all significant variables were subsequently incorporated into a multivariable logistic regression analysis (p<0.05) using backwards selection.
Results
In total 316 patients were treated in line with our inclusion protocol, of which 9 patients were excluded because of missing variables. This left 307 complete cases for the analysis. The incidence of pneumonia was 32% after PhRT compared to 12% after PRT. Baseline characteristics were comparable between the PRT and the PhRT groups except for the surgical variables (time to surgery, technique and anastomosis). Univariable analysis showed relevant association with several variables; radiotherapy technique (PhRT vs PRT) (p<0.01), baseline COPD (p=0.01), age (p = 0.09), surgical access (open vs minimal invasive)(p=0.11) and smoking at baseline (p=0.14). An interaction was identified between baseline smoking and baseline COPD. No confounding was identified between the surgical variables and the radiotherapy technique. At multivariable analysis, only baseline COPD and radiotherapy technique remained significant. The PCA identified 3 components that collectively explained 90% of the variance in the DVH data. If, in the multivariate model, radiotherapy technique was replaced by these three PCA components, PC1 and PC3 were significantly associated with pneumonia, next to baseline COPD (Table 1). PC1 was correlated to the mean dose in both the lungs and the heart, while PC3 was associated with the dose distribution between the low dose (V≤20) and the high dose (V≥20). PC2 was not significantly associated with pneumonia and seemed to represent the distribution of dose between the heart and lungs. In Figure 1, a biplot is illustrated with the relationship between the DVH parameters and PC1 and PC3. The figure, in which each dot represents a patient, highlights the distinctions between photon and proton patients in terms of the significant DVH parameters.
Conclusion:
Radiotherapy technique was significantly associated with (post-operative) pneumonia, next to baseline COPD. A substantial decrease in the incidence of pneumonia was observed in patients treated with PRT. This reduction can be attributed to both the lower mean dose in the heart and lungs (PC1) and the diminished exposure to low doses (PC3) associated with proton therapy, highlighting the benefits of this treatment in minimizing pneumonia risk.