The clinical characteristics of 27 patients were summarized in Table 1. Of all patients, the median age at diagnosis was 61 years (range, 42-72). Five cases (18.5%) were females and 22 (81.5%) were males. Twelve patients (44.4%) had stage IIIA and 15 (55.6%) had stage IIIB diseases. There were 22 cases (81.5%) with central type tumor and 5 cases (18.5%) with peripheral type. Baseline obstructive pneumonitis/atelectasis was observed in 11 patients (40.7%). Mediastinal shift occurred in 3 patients (11.1%) during the course of treatment.
Gross Tumor volume changes
As shown in Figure 2, there was significant tumor shrinkage through the course of treatment. Average GTV volume reduced from 145.1cm3 at fraction 1 to 117.9 cm3 at fraction 17, and the difference was statistically significant (p＜0.001). The median relative GTV reduction was 2.1%, 6.2%, 10.6%, and 11.1% from start to fraction 5, 9, 13 and 17 of therapy, respectively. Greater tumor shrinkage was achieved from fraction 5 to 13, compared with that from fraction 1 to 5 or fraction 13 to 17 (8.5% vs. 2.1% vs. 0.5%). Detailed information about GTV volume change was shown in Table 2.
Dosimetric differences between original and accumulated plans
As demonstrated in Table 3, PTV-GTV coverage were similar between original and accumulated plans. Average V51 of PTV-GTV were 88.2% and 87.6% in original and accumulated plans (p=0.452), with average D95 of 48.1 Gy and 48.0 Gy (p=0.781), respectively. In accumulated plans, only 3 patients (11.1%) showed a relative reduction in V51 above 5% when compared with original plans.
Besides, the D95 and V51 of PTV-GTV were compared between fraction plans (based on CBCT images at fraction 1, 5, 9, 13 or 17) and original plan, which was shown in Supplementary table 1. The results indicated that the percentage of patients obtaining a reduction above 5% in D95 was higher at fraction 5 compared with that at fraction 9, 13 or 17 (18.5% vs. 11.1% vs. 11.1% vs. 11.1%, p=0.448); the percentage of patients obtaining a reduction above 5% in V51 was higher at fraction 5 compared with that at fraction 9, 13 or 17 (22.2% vs. 14.8%, p=0.448; 22.2% vs. 11.1%, p=0.278; 22.2% vs. 7.4%, p=0.129); the percentage of patients obtaining a reduction above 5% in V51 was higher at fraction 9 compared with that at fraction 13 or 17 (14.8% vs. 11.1%, p=0.688; 14.8% vs. 7.4%, p=0.391).
Slight, although statistically significant differences were observed in the lungs’ dosage between original and accumulated plans. The total lung V20 increased from 29.5%±4.2% in original plans to 30.1%±4.1% in accumulated plans (p=0.001), with a median relative increase of 1.6% (range, -3%-9%). The total lung V30 increased from 19.9%±4.4% in original plans to 20.4%±4.4% in accumulated plans (p=0.004), with a median relative increase of 1.9% (range, -3%-16%). Significant difference in the mean lung dose was also observed in accumulated plans (17.0±2.1 vs. 16.8±2.1, p=0.001), with a median relative increase of 1.4% (range, -2%-5%). In accumulated plans, there are 3 (11.1%) and 6 (22.2%) patients obtained a relative increase above 5% in the lung V20 or V30 when compared with original plans.
For the esophagus, an increase was observed in mean (27.1±4.0 vs. 26.6±4.2, p=0.002) and maximal doses (49.5±1.8 vs. 47.4±1.3, p＜0.001) in accumulated plans, with median relative increase of 1.4% (range, -2%-5%) and 4.1% (range, -4%-15%), respectively. Ten patients (37.0%) obtained a relative increase above 5% in maximal dose.
There was no significant difference in the heart mean dose (13.0±6.7 vs. 13.1±7.0, p=0.558), V30 (13.0±10.1 vs.12.9±10.9, p=0.675) or V40 (5.2±5.0 vs. 4.9±5.1, p=0.168) between original and accumulated plans. Seven patients (25.9%) achieved above 5% relative increase in the heart V30 and 8 (29.6%) achieved that in V40.
Predictors of dosimetric differences
Correlations between dosimetric differences and clinical variables were analyzed. Based on the magnitude of tumor shrinkage, 27 patients were divided into two groups: quick tumor regression and slow tumor regression groups. Quick tumor regression was defined as a tumor shrinkage by over 11.1% (the median value of relative GTV reduction), otherwise it was defined as slow. Patients with quick tumor regression showed more notable relative increase in the total lung V20 (median, 2.7% vs. 0.5%, p=0.006), V30 (median, 3.5% vs. 0.2%, p=0.022) and mean dose (median, 2.2% vs. 0.2%, p=0.009) in accumulated plans than those who did not. Besides, in quick tumor regression group, more patients were observed to have a relative increase above 5% in the lung V20 (23.1% vs. 0, p=0.061) and V30 (38.5% vs. 7.1%, p=0.055). Tumor regression also correlated with the differences of the esophagus mean dose (2.2% vs. 0.2%, p=0.009), but not maximal dose (4.0% vs 5.0%, p=0.239). No correlation was found between tumor regression and heart doses change (Table 4). Figure 3 shows a typical case with quick tumor regression. The doses to OARs increased markedly in accumulation plan compared with original plan.
In patients with baseline obstructive pneumonitis/atelectasis, significantly greater relative increase in the total lung mean dose (median, 2.3% vs. 0.4%, p=0.023), lung V30 (median, 3.9% vs. 0.2%, p=0.039) and esophagus mean dose (median, 2.3% vs. 0.4%, p=0.023) was observed compared to those without. Greater increase was also observed in the total lung V20 (median, 3.3% vs. 0.9%, p=0.110), heart mean dose (median, 3.9% vs. 0.2%, p=0.251), heart V30 (median, 8.1% vs. -5.2%, p=0.162) and heart V40 (median, 2.1% vs. -16.1%, p=0.272), despite none of them was statistically significant. Furthermore, in the group with baseline obstructive pneumonitis/atelectasis, more patients were observed to gain above 5% relative increase in heart V30 (54.5% vs. 6.3%, p=0.006) and heart mean dose (36.4% vs. 6.3%, p=0.046) (Table 4).
Mediastinal shift to the ipsilateral side during treatment was observed in two cases with baseline obstructive pneumonitis. Figure 4 showed a typical case with mediastinum shifting to the ipsilateral side as tumor regressed. Increased doses to normal structures were observed, including total lung, esophagus and heart. On the contrary, mediastinal shift to the contralateral side during treatment was observed in a case with baseline obstructive atelectasis (Figure 5). A notable decrease of 10.3% were observed in V51 of PTV-GTV. As for normal structures, decrease was also obtained in doses to total lung, esophagus and heart.
None of other clinical variables, including sex, age, tumor location, presence of bulky mediastinal lymph node or TNM stage, was found to be predictive of the dose differences of PTV-GTV or OARs between original and accumulative plans.