Liver
For the liver subgroup, the initial predicted median PTV coverage (here PTV D
98% and PTV D
95%) before plan adaption was worse compared to lung and prostate but was comparable to lymph nodes and pancreas. One reason might be that less complex shaped (sphere-like) targets, as small lung lesions (lung: mean V
PTV = 15.2 cm
3 vs. liver: mean V
PTV = 38.4 cm
3, see Table
2) or prostate targets, are easier to cover with default baseline plans. After plan adaption, a largely improved PTV coverage was found, which resulted in a close-to-ideal post-adaption PTV coverage, similar to that of the lung cases. With 93.3% of all fractions adapted, liver showed the highest portion of adapted plans (similar to pancreas with 92.0%). This means that the initial target volume coverage using the base plan was not ideal in almost every fraction. After plan adaption, PTV D
98% was > 97.0% of the PD in all fractions. Even though the initial median PTV coverage was worse compared to the lung cases, the initial GTV coverage was similar, which means that the PTV, designed for liver cases in breath hold technique, worked very well. When comparing the normalized percent values of Fig.
3 between these two (or any other) subgroups, especially for the GTV, one has to bear in mind that all liver cases had a stereotactic prescription to the 65% isodose, but only 8/10 lung cases had the same prescription. No significant change in the PTV or GTV near-maximum dose was found, just like for most other subgroups. Regarding OAR sparing, Fig.
2 shows a more or less symmetrical distribution around zero for liver, but with a significantly increased median OAR dose. This is because OAR dose limits were, on average, not fully reached prior to adaption. This tendency can also be seen when looking at the exposure changes of the three most frequently considered OARs (bowel, duodenum, stomach, see Table
4), where mean and median increases in dose for all these OARs were found for liver. During the optimization process, the OAR exposure was fully exploited and brought closer to the dose limits, in order to achieve a very good target coverage without violation of OAR constraint. With a mean number of 33 segments, adapted liver plans were simpler compared to those of lymph node, pancreas and prostate cases.
Lung
For lung cases, the initial PTV coverage of the predicted base plan was better compared to liver, but could still be significantly improved and resulted in a near-optimal PTV coverage after plan adaption. The initial GTV coverage was similar to that of liver, but could still be significantly improved. With 84.4% of all fractions adapted, lung showed similar adaption rates as lymph node cases. Regarding OAR sparing and change of PTV near-maximum doses, similar findings were made as for the liver subgroup. The mean PTV volume of lung cases was the smallest of all subgroups (15.2 cm3) and so was the mean number of segments (26), indicating easy-to-adapt, simple treatment plans.
Pancreas
Plan adaptation resulted in a significant improvement in PTV near minimum dose. Regarding the GTV coverage, no significant improvement could be made on average, when performing online plan adaption. Although the average re-optimized (and even predicted) GTV coverage was acceptable, some cases were observed where sufficient GTV coverage could not be achieved, even after plan adaption, because sparing of OARs was prioritized. This can be seen in Fig.
3, when looking at the relatively large interval between the first and third quartiles compared to those of the abdominal lymph nodes and prostate cases. The large portion of adapted fractions (92.0%) indicates the need for plan adaptation to reduce OAR doses to meet clinically acceptable OAR dose levels. OAR doses could be reduced in more than 75.0% of all OAR constraints of all adapted fractions of the pancreas cases and the median OAR dose reduction was − 87.0% (Fig.
2). The V33
Gy of duodenum, stomach and bowel was reduced on average by more than 80% respectively (Table
4). Without online plan adaption, OAR dose limits would have been frequently violated.
Comparison between tumor entities
All subgroups clearly benefited from online plan adaption in terms of improved PTV coverage. The improved target dose varied between the different tumor entities. To estimate the absolute dose changes of the target volumes achieved by online plan adaption, it is possible to multiply the total prescribed dose of any dose prescription (Table
1) with the corresponding median percent change of any DVH parameter of interest (Table
3) and with the percentage of adapted fractions of the corresponding patient subgroup (Table
2, line 1). Obviously, this formula can only provide a rough estimate of absolute dose changes and does not consider individual patients. Based on the underlying idea of the PTV target volume concept, one would assume that the GTV/CTV coverage physically achieved during dose application is of higher prognostic value than the PTV coverage, since the sole purpose of the PTV margins is to guarantee the GTV/CTV coverage with some degree of confidence. Under this assumption it is possible to identify subgroups that might benefit more from online plan adaption than others. In the present study, the three subgroups liver, lung, and abdominal lymph nodes had the greatest benefit from online plan adaption in terms of improved GTV coverage. After plan adaption, all three subgroups showed excellent GTV coverage (D
98% and D
95%). In addition, a large portion of fractions (> 82%) required re-optimization in all three subgroups, indicating that most of these fractions can be significantly improved by online plan adaption. Since small values of GTV D
98% and D
95% indicate insufficient GTV coverage, these indices can be considered the most predictive (of all DVH parameters examined) in terms of improved tumor control probability (TCP) and possibly LC when comparing non-adapted and online adapted fractions. However, it remains unclear if the significant increases in GTV near-minimum and mean doses will translate into a detectable improved LC.
In addition to the significantly improved GTV coverage in the liver, lung and abdominal lymph nodes subgroups when using plan adaption, these subgroups might also largely benefit from the breath-hold and automated beam gating capabilities of the oMRgRT system, since no internal target volume concept is needed. An internal target volume concept would increase the total irradiated volume [
51], especially for these cases, where breathing-related motion of target volumes can be frequently seen. In this study, the influence of beam-gating was not investigated and no motion range assessment was made for the target volumes. That is beyond the scope of this study.
It was found for pancreas, that the plan adaption capabilities were largely used to reduce OAR doses to an acceptable level. Although the re-optimized GTV coverage was acceptable in most cases, the improvement in GTV coverage via online plan adaption was not as large as in the other subgroups, as OAR sparing was prioritized. In contrast, in the prostate subgroup, only 69.4% of all fractions were considered for re-optimization. For most of these fractions, the initial CTV coverage was quite good but could still be slightly improved when adapted. Ultimately, few fractions were found, where the initial PTV and CTV coverage was unacceptable. For these fractions, online re-optimization resulted in an excellent CTV coverage. In summary, for prostate cases, the benefit of online re-optimization was found to be not as systematic as for the liver, lung, abdominal lymph nodes and pancreas cases. In each subgroup, at least one of the primary dosimetric endpoints defined under “
Methods” (significant increase in GTV/CTV near-minimum and mean dose, and significantly reduced OAR exposure) was achieved (Table
3). Except for pancreas, all other subgroups met all primary endpoints related to improved GTV/CTV dose.
To the best of our knowledge, up to now, no attempt has been made to quantify the influence of MR-guided online plan adaption on DVH-related parameters and systemically compare the results between multiple subgroups with different tumor entities typically treated on integrated MR-Linac systems. Our intent was to provide information for a more informed decision making when assigning patients to the (still very limited access) MR-Linac. Henke et al. [
40] analyzed 81 online adapted fractions (20 patients) in a patient cohort of mixed oligometastatic or unresectable abdominal malignancies (hepatic lesions, adrenal metastasis, pancreatic adenocarcinoma and lymph node metastases). The overall adaption rate (83.5%) was comparable to our study, although less liver fractions (66.0%) were adapted compared to our liver subgroup (93.3%). Similar to the present study, several fractions among the pancreas cases were found, where GTV dose de-escalation was necessary due to OAR proximity of the tumor. Regnery et al. [
52] prospectively compared predicted versus adapted dose distributions in 154 online adapted fractions in 21 lung tumor patients. The higher adaption rate of 93.3% compared to 84.4% in the current study can be explained with the large number of ultracentral lung tumors in the cohort of Regnery et al., where OAR violations are more likely to occur due to adjacency OARs. Regnery et al. found a large increase in the minimum biologically effective dose (BED) of the PTV and a moderate increase in the minimum BED of the GTV. We observed the same tendency when considering PTV and GTV D
98% or D
95%. In the same study only small increases in mean BED inside the PTV and GTV were found, which is also in accordance with our findings of PTV and GTV D
mean. El Bared et al. [
35] evaluated the dosimetric benefits in 10 patients treated for unresectable pancreatic cancer on a cobalt-60, 0.35 T MRI system when performing online plan adaption and reported outcome. Although comparability to our study is limited due to a fundamental discrepancy in technical design and beam quality (tri-source cobalt-60 vs. 6 MV flattening filter free Linac), El Bared also found improved PTV coverage when performing online plan adaption. However, the influence on GTV coverage was not evaluated. Placidi et al. [
37] found a similar trend of improved PTV coverage in 8 pancreatic cancer patients also treated on the cobalt-60 system and similarly reported increased CTV dose after plan adaption. The influence on GTV coverage was not evaluated. Mayinger et al. [
53] analyzed online adapted treatment plans of 15 patients with liver metastases and found improved PTV coverage in cases where the target volume was in close proximity to OARs. The influence on GTV coverage was not evaluated in detail. In the present study, we did not stratify patients for adjacency of OARs, but when looking at the PTV mean and near-minimum doses, we also found a significant increase after plan adaption in liver cases. Padgett et al. [
43] artificially created adapted plans for 10 patients with liver cancers on the cobalt-60 system and compared the results to the non-adapted plans and also found improved PTV and GTV coverage as well as a reduced number of OAR violations (duodenum, bowel and stomach) after plan adaption. We observed the same trend regarding target volumes and reported small mean and median dose increases for OARs like duodenum, bowel and stomach. This is no contradiction to the findings of Padgett et al. since OAR sparing was prioritized over target volume coverage in our study and no hard OAR constraints were violated during plan adaption.