As shown in , our average original proton treatment plans adequately covered the CTV with minimal variation in normal tissue doses, as confirmed by the expiration and inspiration phase data sets. The verification plans using 4-D-generated images in the expiration/inspiration phase using a simulated CT data set showed that average and individual CTV coverage remained at about 99%, indicating that our original plan was sufficient to take intrafractional tumor motion into consideration.
Dose–volume data for original proton therapy plan and verification using the end of expiration and inspiration phases
When the original plans were applied to weekly 4D-CT images over 7 weeks in all 8 patients, CTV coverage was compromised in selected cases. Particularly, alignment using skin markers only during the 7 weeks of proton therapy resulted in substantial CTV target misses, although variation in the normal tissue DVHs remained within 2.4% (). The average CTV coverage dropped from 99% to 95%, with some cases having as little as 75.5% coverage. However, the average and individual CTV coverage was higher (97.9%) when alignment using bony structures, rather than skin markers only, was used, indicating the crucial role of a daily on-board X-ray image (). The CTV prescription coverage in the repeated 4D-CT plans using bony structure alignment was, however, as low as 90.9% for 1 patient because of anatomic changes and motion variation during the 7 weeks of treatment (see Discussion).
Comparison of dose–volume data between original plan and recalculated, repeated weekly four-dimensional computed tomography plan using alignment with skin marker registration or with bony structure
Using bony registration, the total lung V5, V20, and V30 values and the mean dose increased by 2.2%, 1.4%, 1.3%, and 0.7 Gy, respectively, compared with original planning at simulation, over 7 weeks of treatment. The heart V40 increased by 1.5%, and the esophagus V55 increased by 0.8%. Among the normal tissues, the spinal cord maximum dose exhibited the largest variation, increasing by 4.4 Gy. The average DVH variation between the original plan and the weekly 4D-CT plans was within 2.5%. When the expiration phase and inspiration phase dose distributions in the repeated plans were compared, the V5, V20, V30, and mean dose in the lung were consistently higher in the former, which was as expected because the lung volume is larger in the inspiration phase than in the expiration phase. This difference in dose distribution between the two breath phases was not seen in the CTV or in other normal tissues. In addition, compared with ipsilateral lung, the increase of the V5, V20, V30, and mean dose over 7 weeks was higher in the contralateral lung.
A representative case showing typical isodose distributions in the transverse and sagittal planes of the planning CT data set and 7 weekly CT data sets in the expiration and inspiration phases is shown in . The prescription dose lines (yellow) did not show large variation among the seven weekly CT data sets in either the expiration or inspiration phase. The 10-Gy line only appeared at the anterior region of the contralateral lung in the planning CT data sets, but spread to other contralateral lung regions in the weekly CT data sets. The 45 Gy and 20 Gy lines also showed some variation at the anterior region of the contralateral lung but exhibited little variation in other regions. In the sagittal planes of the inspiration phase CT data set, the diaphragm position varied widely, which indicates the irregularity of the patients’ breathing during the course of the treatment.
Fig. 1 Isodose distribution, dose volume and density changes in a typical case during 7 weeks of radiation therapy. (A). The dose distributions in transverse and sagittal planes of the planning computed tomography (CT) scan and seven weekly repeated CT scans (more ...)
shows the DVHs of CTV and normal tissues for the representative case and their variation (DVH variation band shown as the shaded region) over 7 weeks of repeated 4D-CT plans. The DVH variation band for the CTV was very narrow, just outside the original DVH line. The DVH variation for the contralateral lung was above the original DVH lines, whereas the DVH variation bands for the total lung and ipsilateral lung were symmetrically distributed around the original DVH lines. The DVH variation bands for the spinal cord, heart, and esophagus were also wide and consistently above the original DVH lines, which means that the irradiated volume of these organs was often larger in the repeated 4D-CT plans than in the original plan. These data show minimal variation in CTV coverage but a systematic increase in dose to the contralateral lung, heart, spinal cord, and esophagus in a typical case over 7 weeks of radiotherapy.
Because proton dose is very sensitive to changes in density, and because tumor density may change during 7 weeks of treatment, we analyzed the correlation between the CTV density change resulting from tumor shrinkage or anatomic variation and the normal tissue DVHs histograms. In , we plotted the scaled average density of CTV and the scaled mean dose to the contralateral lung for the representative patient during the 7 weeks of radiotherapy. For all endpoints, the scaled endpoint for each week was calculated by dividing the value of the weekly endpoint by the value of the endpoint for the first week. The scaled endpoint is used to bring different endpoints to the same scale in one graph to show the correlation between two or more endpoints. Interestingly, the CTV density fluctuated over 7 weeks. Over the first 3 weeks of treatment, radiation may have caused the tumor to shrink, resulting in a decrease in the CTV density. However the CTV density appeared to increase from week 3 to week 4 before continuously decreasing again, with small fluctuations. The increase in CTV density may have been caused by radiation-induced inflammation, and the fluctuation in CTV density over the 7 weeks of radiotherapy may have been caused by the combined effects of tumor shrinkage and radiation-induced inflammation. There was a close inverse correlation between average CTV density and contralateral lung mean dose over 7 weeks of treatment with proton therapy planning. However there was no such trend or correlation in the same patient when IMRT (photon) therapy planning was conducted, indicating that protons are much more sensitive to density changes than photons (). When data from all 8 patients were analyzed, a similar trend for inverse correlation between CTV density and contralateral lung mean dose was observed (). The correlation between CTV density and other critical structures, such as the spinal cord, heart, esophagus, and ipsilateral lung, for all 8 patients is also shown in . The spinal cord maximum dose continued to increase, whereas the heart V40, esophagus V55, and ipsilateral lung mean dose exhibited relatively smaller fluctuations.
Fig. 2 Correlation between average scaled clinical target volume (CTV) density change and affected normal tissue endpoints over 7 weeks of radiotherapy for all cases. Average scaled CTV density of (a) contralateral lung mean dose (b), spinal cord maximum dose (more ...)
shows a case involving compromised CTV coverage resulting from interfractional tumor motion and anatomic changes. Although the patient was aligned on the basis of bony structures, a substantial alignment error was observed for the GTV and CTV over soft tissue in Week 7 (). When proton therapy planning was conducted, compromised CTV and IGTV coverage was observed, with the prescription isodose line (63 Gy, yellow line) broken over GTV and CTV and substantial increased contralateral lung dose. As shown in , coverage of the CTV was reduced from 99% to 90.9%, and the contralateral lung and esophagus dose increased between the planned DVH and the DVH calculated at Week 7. However, when IMRT planning was conducted, there was no reduction in IGTV and CTV coverage, and the contralateral lung dose was not increased ().
Fig. 3 Selected case with compromised target coverage and increased normal tissue dose with proton therapy, but not with intensity-modulated radiation therapy (IMRT), caused by significant motion/anatomic changes during 7 weeks of radio-therapy. (a) Target miss (more ...)