IMRT is an elegant technique for the treatment of children and allows a reduction of the high dose of radiation delivered to the tissues surrounding a tumor. To our knowledge, this article is the first publication to describe a dose comparison between tomotherapy and 3D-RT in neuroblastoma and is the third to compare IMRT and 3D-RT [14, 15]. For pediatric irradiation, three goals have to be pursued: tumor control, avoidance of complications or sequellae and a decrease of the secondary radiation-induced cancer risk.
Because the contralateral kidney was close to the surgical bed and there was a need to deliver a homogeneous dose in the vertebrae, the PTV-V95% constraint remains challenging with 3D-RT. In this series the PTV-V95% constraint was achieved in 6 cases on 7 with HT compared to 2 cases only with 3D-RT. Furthermore, to obtain the best dose distribution with 3D-RT, the irradiated volumes are high, as demonstrated by the conformity index, which is approximately two-fold greater with 3D-RT compared to HT, (1.2 vs 2.9). Thus, HT achieved the first goal of pediatric irradiation, i.e., the possibility of better local control by improving the dose-to-tumor distribution. Conformity was already improved with other IMRT technique . Although the risk of early or late complications at this dose is low, dose distribution to different organs have to be discussed, i.e., the kidneys, vertebrae. Because these young children also receive cisplatin, a well-known nephrotoxic agent, minimizing the radiotherapy dose to both kidneys is important because it may translate to less organ dysfunction. Differentiation has to be made between children with one or two remaining kidneys.
In cases in which the ipsilateral kidney had been removed, the shielding of the contralateral kidney must be strict. In our study, the overall values were very low and always below the dose thresholds for both radiotherapy techniques, and we did not observe statistically significant differences in the mean doses and V12 values between the two techniques. However, the V12 values were 18% lower for HT than for RT3D. In contrast, the average values were 50% higher for HT than for RT3D, i.e., 3.3 Gy and 2.2 Gy, respectively. This increasing of the dose with IMRT was described by Shaffer et al, but our figures were lower than those reported by these authors. The reason is probably that their children were treated with higher dose than in our series .
For the cases in which the homolateral kidney had been preserved, the main advantage of the IMRT could be its shielding of part of the remaining ipsilateral kidney, thus decreasing its risk of postirradiation involution. For the kidney ipsilateral to the tumor, the mean average dose was reduced by 17% with HT compared to 3D-RT, and the mean V12 Gy was reduced by 43%. Some explanations for the lack of a more striking difference in shielding with HT include the following: (1) the need to irradiate vertebrae at higher doses than could be administered to avoid inhomogeneous growth of the bone and increase the dose to the contralateral kidney; and (2) technical reasons related to the tomotherapy system. To obtain a homogeneous dose in the target volume (PTV), the multileaf is opened to one size of the collimator width before and after the appearance of the target volume in the beam. This opening is total, i.e., not progressive. Thus, because we used 2.5 cm of collimator width, the size taken into account for irradiation was increased by 2.5 cm below and above the PTV in the cranio-caudal direction. Thus, compared to 3D-RT, the total beam’s cranio-caudal size was relatively higher with HT. Another point can be discussed is the motion of kidneys according to the respiratory control. A recent study concluded that the renal motion is highly correlated to age and weight of the child and diaphragmatic motion. However, authors concluded that, because of the low absolute magnitude of renal motion, the role of respiratory gating in younger children is limited .
Skeletal problems when using IMRT can be minimized by including adjacent vertebrae into the PTV. In a large series of children treated for Wilm’s tumor, Paulino et al differentiated children according delivered dose. RT dose was 1000–1200 cGy (Group A) in 12, 1201–2399 cGy (Group B) in 11, and 2400–4000 cGy (Group C) in 19. The 10- and 15-year actuarial incidences of scoliosis for Group A and B patients were 37.7 ± 12.4% and 37.7 ± 12.4%, whereas for Group C patients the incidences were 65.8 ± 12.0% and 74.4 ± 11.7% (p = 0.03) . Although conventional 3D-RT delivers a somewhat homogeneous dose to the spine, HT with inclusion of the adjacent spine in the PTV offers the same homogeneous dose distribution, with no difference in mean doses. However, with the same dose distribution, the kidneys were better shielded, and the target volume, i.e., PTV, was better covered. Our conclusions are comparable with the previous comparison of 6 children published by Paulino et al  and cases analyzed by Shaffer et al; . This is in accordance with Paulino et al study which advocated the inclusion of vertebrae in the CTV, in order to reduce dose heterogeneity and therefore reduce the incidence of skeletal growth deformities . Even if Plowman et al attempt to demonstrate the contrary and advocate an increasing of integral dose by inclusion of vertebrae in the CTV, we cannot prove this assertion .
The goal of preventing radiation damage is crucial, particularly in children less than 3 year-old. However, radiation-induced carcinogenesis is not simply the result of mutations of stem cells. Several factors can confuse radiation causality, and sporadic cancer, genetic factors, lifestyle (including exogenous factors) and radiological irradiation are largely used for follow-up . The role of the delivered dose is controversial. Proponents of a linear (no-threshold) relationship believe that the carcinogenic effect of any dose can be assessed by this relationship, while others claim that the role of low doses is underestimated because they do not take into account bystander effects. Conversely, radiobiologists and radiation oncologists have concluded that clinical experiences have not confirmed these allegations, and moreover that these low doses could induce an adaptive response in cells by stimulating the efficiency of DNA-repair capacities. In this study, body volumes receiving 1 to 5 Gy were significantly larger with HT than with 3D-RT. However, volumes receiving 7 and 10 Gy were equal between both techniques, and volumes receiving doses higher than 10 Gy were significantly smaller with HT than with 3D-RT. The difference of dose distribution is clearly related to the dose for all organs, with larger volumes irradiated at low dose with IMRT and larger volumes irradiated a high dose with RT-3D. The pathology type of the secondary tumors probably depends on the dose; The results already published based on this population demonstrated that the magnitude of the radiation dose received at the site of origin increased the risk of an second malignant cancer . Thus, sarcoma occurs in the tissues receiving the highest dose [7, 20]. Dose levels at which SMN are most likely to occur have not yet been clearly established. Kirova et al.  showed that most reported cases of radiation-induced sarcomas after breast irradiation occurred at sites that had received doses of 60–80 Gy, with a minimal dose of 10 Gy. Dörr and Herrmann  reported that the majority of second tumors occurred at sites that had received <6 Gy and were located within the margin region of the planning target volume (PTV), defined as the volume from 2.5 cm inside to 5 cm outside the margin of the PTV.
In a report on second malignancy in the United States, Wilms et al. showed that it is important to reduce the volumes receiving 20 Gy or more to decrease the risk of secondary cancers . In our series, even if prescription doses were relatively low, i.e. 21 Gy, we show that HT should provide this opportunity by the decrease of the CI from 2.97 with 3D-RT to 1.57 with HT. Having demonstrated that the majority of second cancer had developed within volumes exposed to intermediate doses, Diallo et al suggest that tomotherapy and linear accelerator IMRT may increase the risk of second cancers by increasing the volume of intermediate dose regions. These results should be taken into account in the RT strategy .
It should be remembered that the issue of radiation-induced carcinogenesis is not without controversies. In particular, the phenomenon of radiation hormesis at low-radiation doses has attracted increasing attention . Radiation hormesis is considered to be an adaptive response to the external stress of radiation exposure and is manifested in several cell lines in the form of reduced chromosomal aberrations and increased longevity. Extrapolating risk of radiation-induced carcinogenesis is an uncertain exercise. Data on radiation carcinogenesis are mainly derived from retrospective studies, with variable patient populations exposed to variable radiation doses whose dosimetry is often uncertain. In addition, a heightened risk of second malignancies may exist in these patients. In an extensive review of the literature, Suit et al. concluded that the experimentally observed heterogeneity in secondary induced-cancer risk indicates a large genetic role in determination of risk in the individual . Furthermore, due to the quite large and undefined heterogeneity in the patient populations studied, no precise quantification of the risk of radiation-induced secondary cancer is available at present . Most of the second cancer arising from irradiated volumes are not are not usually classified as radio-inducible cancers. Even if consequences in terms of second cancer are not yet a high-priority issue for radiation oncologists (comparing to the control of the cancer and the survival of patient), lowering the distant doses remains an important public health issue and a major challenge for RT in the future. A better understanding of dose distributions, inducible second cancer, for each organ, is necessary to perform dosimetry with real dose constraints to protect the development of second cancers. Also, prudence principle is required. In this goal, radiation oncologists are able to demonstrate some advantages of IMRT compared to 3D-RT.