There is growing evidence that highly conformal irradiation modalities, like different IMRT approaches, may improve critical organs sparing by improving conformity [6, 7, 12–15], with potentially clinical significant consequences in haematological malignancies.
The open question is whether IMRT might lead to a lower dose to the surrounding organs and whether the rate of late complications (in particular lung and cardiac toxicity) could be really reduced with IMRT.
In this comparative planning study, we evaluated different photons IMRT solutions applying the INRT concept, in comparison with the actual reference technique 3D-CRT.
Helical Tomotherapy and VMAT were tested as very highly conformal techniques for PTV coverage, with also the potential advantage of a faster delivery solution for VMAT (one rotation only). B-VMAT was specifically developed in our Institution for HL patients with mediastinal involvement, in order to achieve a highly conformal solution lowering radiation exposure of lungs and breasts. TD represented a feasible and simple alternative planning solution for Tomotherapy if a low degree of modulation is desired.
All different IMRT techniques were able to better conform the dose to PTV compared to 3D-CRT, even if the standard 3D-CRT approach lead to a valid target coverage, satisfying ICRU criteria (V95%> 95%); better PTV coverage achieved by IMRT is depending of course on the IMRT ability, regardless of different technical approaches, to modulate the intensity of each radiation beam, resulting on a higher conformal delivery of radiation dose to PTV. Among different IMRT techniques, HT and VMAT showed the best level of conformity to PTV (Table 2, p<0.05 for CN); VMAT and B-VMAT had higher values of the maximum dose (V107%), however better results in terms of homogeneity of dose inside PTV are promised for future version of Monaco software. All different IMRT solutions were also better in terms of lowering mean doses to certain OAR (thyroid gland, heart and coronary ostia,), as already shown by other Authors in similar planning comparison studies[7, 12, 13]. For such organs, in which probably a lower mean dose is potentially correlated to a lower incidence of late toxicity, IMRT confirms its advantage in our series, with all different modulated techniques able to better spare thyroid gland; it is reasonable that lowering the radiation dose to the thyroid gland could reduce the risk of late toxicity as hypothyroidism and second cancer .
A substantial avoidance of heart and coronary ostia has been however achieved independently from IMRT, by simply applying the INRT concept other than the wider IFRT approach (in 8 out of our 10 patients, these structures received very low doses), as previously shown by Koeck et al. , reporting no significant difference in cardiac Dmean between 3D-CRT and IMRT when using INRT. Some authors stated that the aim of heart sparing could be best achieved with IMRT . Anyway, the individual magnitude of clinical benefit related to a possible IMRT dosimetric gain is hard to predict, mainly depending on adjunctive risk factors (patient anatomy, entity of mediastinal involvement, cardiac comorbidity). In the near future, at least in critical anatomical presentations and in clinical cases at risk for cardiac toxicity, new different approaches, such as proton therapy, could probably further reduce cardiac radiation doses (a strong reduction of heart exposure as well as of radiation doses to critical cardiac subunits was reported by Hoppe et al. ).
One of the aims of IMRT in supradiaphragmatic HL patients is to reduce radiation exposure to lungs; Dmean to lungs was similar for all different technical approaches, including 3D-CRT; all IMRT techniques were able to significantly reduce volumes receiving high doses (>20 Gy); this could be expected to translate into a lower incidence of acute radiation pneumonitis (Girinsky et al.  reported a grade >2 lung toxicity in 10% of the cases with mean dose of 12.8 Gy and in 5% with average V20 of 25% in treating HL patients with mediastinal masses). Opposite to a reduction of V20 values, IMRT techniques resulted in an increase of V5 parameter. For low doses pulmonary volumes (V5), higher was the CN of each different technique, higher were the corresponding V5 values; on the other hand, there was an inverse correlation between CN and lungs V20 (as the CN decreases, higher V20 values are obtained). The slope of the correlation curves shown in Figure 3 suggests that the CN achievable with different techniques could be considered as a potential endpoint (the best compromise between low and high doses volumes) for planning.
The impact of low dose radiation exposure to large breasts’ volume on the risk of developing a secondary cancer is currently unknown; there are some clear data showing a risk reduction with lower doses and smaller volumes , but there are still uncertainties on which dose distribution to the breasts is the most conservative . Comparing Dmean between 3D-CRT and IMRT we find comparable results; in our experience the B-VMAT solution, specifically designed as our class solution for lymphoma patients involving the mediastinum, seems to be the most appropriate, obtaining Dmean values of 0.7 Gy (little bit lower than those achieved with other planning solutions, p<0.05). Dmean values obtained in our study with all different techniques are in any case comparable to those reported in other experiences , even if with a broad range of V4 and CN values, strongly dependent on patients’ specific anatomy (Figure 3).
The dose to non-target tissue did not significantly vary among all different techniques (slightly higher for techniques with higher CN values).
Although some experience are reported in literature  about the comparison of treatment plans resulting from optimization methods based on physical dose or biological parameters, the present study is the first experience evaluating volumetric IMRT techniques based on radiobiological planning in treating HL patients, as well as the first experience comparing them with Tomotherapy-based solution (classical HT); radiobiological optimization, specifically part of the Monaco IMRT planning process, was able to respect all dose constraints and to obtain satisfactory dose distribution, both for PTV coverage and OAR’s sparing. A planning option that has not been investigated in the present study, but that can achieve similar dose distribution, is traditional IMRT with equidistant fields, an approach already tested by other groups with the use of 9 static coplanar IMRT fields .
IMRT reduces high doses to OAR to a varying degree, depending on prescription strategies and target paradigm, at the cost of larger volumes irradiated to low/intermediate doses, whose clinical significance is nowadays unknown. Considering all different OAR’s together, we were not able to find out an optimal IMRT technique, with constantly better dosimetric performances; one of the reasons could stand in the anatomical differences between 10 included patients, as well as in the INRT approach itself, able to achieve a good sparing of most OAR even with less conformal techniques . In this setting, IMRT represents a continuum of possible dose distributions, being the choice of the specific technique apparently of minor importance. In our clinical routine the decision to use IMRT or not is made on an individual basis after comparative treatment planning, with the largest benefit to be expected in patients with large mediastinal targets.
A future generation of studies would probably consider different IMRT solutions for different disease presentations at diagnosis, including second cancer risk modeling in the planning process.