Palliative (chemo)radiotherapy is an important component of care for many patients with NSCLC . Sequential plus concurrent palliative chemoradiotherapy improves survival compared with chemotherapy alone , but it increases toxicity, particularly radiation esophagitis. More than 85% of the patients receiving chemoradiotherapy in the CONRAD study reported various degrees of esophagitis, but none reported grade 4 . Validated predictors of esophagitis for clinical use in this population are lacking. In the curative setting, an individual-patient-data meta-analysis has been performed . Factors predictive of esophagitis grade ≥2 and grade ≥3 were assessed. Most patients received platinum-containing regimens. The development of esophagitis was common, scored as grade 2 in 32%, grade 3 in 17%, and grade 4 in 1%. On univariable analysis several baseline factors were statistically predictive of esophagitis, but only dosimetric factors had good discrimination scores. On multivariable analysis, the esophageal volume receiving ≥60 Gy (V60) alone emerged as the best predictor of grade ≥2 and grade ≥3 esophagitis. Additional research is needed for palliative scenarios, which typically employ hypofractionated regimens with moderate total doses (often 30-45 Gy). Despite dose reduction, esophagitis influences quality of life and might cause weight loss, treatment interruption and, in severe cases, hospitalization .
The RTOG 0617 study compared curative standard-dose (60 Gy) versus high-dose (74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III (NSCLC) . The study used a 2 × 2 factorial design with radiation dose as one factor and cetuximab as the other. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3% and 5% of patients in the 60-Gy-arm versus 12% and 17% in the 74-Gy-arm, respectively (p=0.0005 and <0.0001). Factors associated with improved overall survival on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, PTV and heart V5. Thus, this study supports treatment planning efforts leading to lower esophageal and heart doses.
The aim of our study was to identify predictive factors for acute esophagitis in the non-curative setting. We reviewed the treatment planning and clinical data, and decided to dichotomize esophagitis (yes/no), because its overall incidence was limited and few patients developed grade 3 toxicity, meaning that the statistical power of separate analyses for grade 2 or 3 would have been very limited. The grading was based on retrospective chart review, a limitation which is shared with many previous studies, which might lead to underestimated rates of mild toxicity. Prospective assessment, as done in the CONRAD study, would have provided more detailed information about the patients’ nutrition status and symptom burden. Because almost all treatments employed 2.8 – 3.0 per fraction, we did not convert doses to biologically equivalent doses, such as EQD2.
In line with previous research, we found associations between several dosimetric factors and risk of esophagitis. The most important of these risk factors was maximum dose to the esophagus. As illustrated in Figure 1, doses lower than 35 Gy are recommended (as low as reasonably achievable without exceeding lung and spinal cord tolerance). However, the presence of N2 and N3 lymph node metastases might complicate sparing of the esophagus, due to anatomical proximity, even if 3-D conformal techniques are replaced by intensity-modulated and/or arc-based approaches [21-24]. In own patients with high Dmax, a reduction of Dmean was associated with lower rates of esophagitis. It is known from previous studies that concomitant chemoradiotherapy increases esophageal toxicity, as also seen in our analysis. Unexpectedly, concomitant oral steroids reduced the risk of esophagitis. Unless confirmed in a prospective trial, one has to consider the influence of confounding factors and possible interactions between steroid use and lack of chemotherapy or prescription of lower doses of radiotherapy. Given that many of our patients had stage IV NSCLC it appears possible that other concomitant medications were used, e.g. analgetics, which were not captured in this study. Baseline use of analgetics would probably mask the symptoms from mild esophagitis, especially if not evaluated with prospectively administered patient questionnaires.
A recent single arm trial (ICORG 06-34) studied 3-D conformal radiotherapy to reduce the toxicity of palliative lung irradiation . Fractionation regimens included 39 Gy in 13 fractions, 20 Gy in 5 fractions, and 17 Gy in 2 fractions. The primary endpoint was the occurrence of grade 3 or higher esophagitis (CTCAE v4.02). The mean dose to the irradiated esophagus, defined as one centimeter above and below the PTV, should be ≤30% of the reference point dose, unless the PTV was extending into the esophagus. Overall, 30 patients could be analyzed (22 treated with 20 Gy, 12 with 39 Gy, 1 with 17 Gy). For the 39 Gy regimen Dmax was 23-42 Gy (mean 38 Gy), while the mean dose to the irradiated esophagus was as intended (mean 23 Gy). No grade 3 esophagitis was recorded. Grade 2 toxicity did not exceed 11% either. Due to contouring difference (irradiated vs. whole esophagus) and study design (prospective vs. retrospective) these data are difficult to compare to ours. Nevertheless, both studies suggest that efforts to spare the esophagus should be pursued. In the future, larger databases should be established in order to develop more advanced prediction models. As a consequence of Figure 1, our current treatment planning strategy is to limit Dmax to the esophagus, e.g. by accepting a PTV coverage of <95% at the intersection with the esophagus. If a high Dmax is unavoidable, we try to reduce Dmean.