This article is an openaccess article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
The aim of the present paper is to compare the integral dose received by nontumor tissue (NTID) in stereotactic body radiation therapy (SBRT) with modified LINAC with that received by threedimensional conformal radiotherapy (3DCRT), estimating possible correlations between NTID and radiationinduced secondary malignancy risk. Eight patients with intrathoracic lesions were treated with SBRT, 23 Gy × 1 fraction. All patients were then replanned for 3DCRT, maintaining the same target coverage and applying a dose scheme of 2 Gy × 32 fractions. The dose equivalence between the different treatment modalities was achieved assuming α/β = 10Gy for tumor tissue and imposing the same biological effective dose (BED) on the target (BED = 76Gy_{10}). Total NTIDs for both techniques was calculated considering α/β = 3Gy for healthy tissue. Excess absolute cancer risk (EAR) was calculated for various organs using a mechanistic model that includes fractionation effects. A paired twotailed Student
Three Dimensional Conformal Radiation Therapy
Biological Effective Dose
Clinical Target Volume
Dose Volume Histogram
Excess Absolute Risk
Equivalent Integral Dose
Gross Target Volume
Integral Dose
Intensity Modulated Radiation Therapy
Normal Tissue Integral Dose
Non Tumor Tissue
Organ at Risk
Organ Equivalent Dose
Planning Target Volume
Risk Equivalent Dose
Stereotactic Body Radiation Therapy
Treatment Planning System
Radiotherapy has been often described as a “two edged sword” because, if on one hand it is a major modality of cancer treatment, but on the other it can be a cause of cancer. During the past decade, radiationinduced secondary malignancies have become a major concern and recent studies have shown that radiotherapy treatment is associated with a small, though statistically significant, enhancement in the risk of secondary cancers. At present it is generally agreed that around 10% of patients may develop a second malignancy due to radiation therapy, even if this number is not known with much certainty and could range between 6% and 13% [
Modern radiotherapy techniques are moving in the direction of optimizing the dose conformation to tumors meanwhile sparing the exposure of organs at risk and minimizing the radiation load to healthy tissues; this is usually obtained by improving patient positioning, target localization and providing sharp dose gradients. In this context, new highprecision technologies like intensity modulated radiotherapy (IMRT) and SBRT represent major advances in cancer treatment. The high degree of conformity associated with these techniques is often obtained by increasing the number of fields and using fixedshape or dynamic conformal arc beams. This has important implications in the debate over the possible increase of secondary cancers due to radiation therapy, essentially for two reasons. Firstly, delivery of a specified dose from these special techniques requires the accelerator to be energized for longer (more monitor units are needed) and, as a consequence, the total body dose due to leakage radiation is increased by a factor of two or three [
The increase of energy deposition in healthy tissues might play a leading role in the induction of secondary cancers, especially in the light of past and recent literature data which show a possible correlation between integral dose and secondary malignancies [
The aim of this work was to compare the integral dose (ID) imparted by SBRT and 3DCRT and establish possible correlations between integral dose calculated from differential DVHs and the increase of carcinogenic risk.
The ID attempts to describe energy deposition within the whole body and it is historically considered as a physical quantity capable of representing the “physical aggression” and risk of complications due to radiation therapy. Integral dose is the product of mass of tissue irradiated and absorbed dose. Although it is generally accepted that normal tissue complication risk and secondary malignancies risk increase as the ID increases, ID is rarely used in clinical practice to compare competing plans or to evaluate treatment outcome. At present, it is still unknown which increase of integral dose could be considered clinically acceptable; however, as a general rule, it is recommended to keep ID to a minimum, tumor dose being fixed and provided that normal tissues are not unacceptably compromised [
To our knowledge, there are no studies investigating ID in stereotactic body radiation therapy and comparing SBRT with “traditional” techniques. Generally, SBRT does not lead to unacceptable side effects if the serial organs are excluded from high dose regions and the organs at risk constraints are respected. Most importantly, we wondered whether an increase of ID may be related to an increase in secondary cancer risk. This issue is not trivial since ID calculation does not consider fractionation effects, which are supposed to play a key role in radiationinduced malignancies.
Furthermore, the induction of secondary cancers is a matter of interest in SBRT as the use of this technique might be extended to patients who live for many years after radiotherapy. Given the very encouraging results with the SBRT technique, phase III studies are in fact strongly needed in order to compare SBRT with surgery in operable patients [
The integral dose ID to an organ
where
By changing the fractionation scheme of a certain treatment plan, the ID also changes. The basic mathematics of fractionation change are given in the Appendix. Combining Equation (2) with Equation (A5) (Appendix), it is possible to calculate the integral dose for a given fraction regimen which is biologically equivalent to another fractionation scheme; the new integral dose to an organ
There is great uncertainty regarding the doseresponse relationship for induced secondary cancers in radiation therapy [
At present, simple models that predict risk for radiationinduced malignancies for radiation therapy are based on conventional concepts derived from radiation protection. In particular, a linear extrapolation of cancer risks from intermediate to very low doses appears to be the generally accepted methodology in ICRP [
Nevertheless, radiation protection models have to be applied with extreme care to radiotherapy patients, since doses and dose rates are quite different from those received by Abomb survivors. In fact, Abomb survivors received a single dose exposure of radiation, whereas radiotherapy patients receive fractionated therapy over an extended period, thus allowing for some repair of DNA damage. Further, above 1 Gy, the Abomb survivor data are better fitted by linearquadratic or linearquadraticexponential models [
In the past, different authors have used the doseresponse relationship for Abomb survivors to assess induced secondary cancers in radiation therapy by applying a correction doserate effectiveness factor (DREF) to take into account exposure to different doses and dose rates [
In the present study secondary cancer risk estimations were performed applying the mechanistic model proposed by Schneider
The model is based on the linearquadratic formalism, where inductions of carcinomas and sarcomas are modeled separately and described in terms of analytical functions. The linear quadratic model of cell kill is combined with the linearnothreshold model for radiation induced cancer at low dose in order to determine a possible doseresponse relationship for radiationinduced solid cancer for radiotherapy doses.
According to this approach, for any threedimensional inhomogeneous dose distribution, the excess absolute risk (EAR) can be calculated using the formalism described in [
According to the model proposed by Schneider
The sitespecific parameter β is taken from [
In this form the function
Parameters used for EAR calculation according to Equations (4)–(7). For each organ, the parameters β (expressed as excess case per 10,000 PY/Gy),
Organ  Β * 


α/β (Gy) 



3DCRT  SBRT  
All Solid  74.0  −0.024  2.38  3  0.17  0 
Lung  8.0  0.002  4.23  3  0.83  0 
Rectum  0.73  −0.024  2.38  3  0.56  0 
Esophagus  3.2  −0.002  1.9  3  0.50  0 
Small Intestine  10  −0.056  6.9  3  0.09  0 
Liver  2.4  −0.021  3.6  3  0.29  0 
Bladder  3.8  −0.024  2.38  3  0.06  0 
The risk equivalent dose,
In the limit of
The repopulation parameter
Eight patients with intrathoracic lesions were planned and treated with SBRT with a singledose of 23 Gy. The integral doses to PTV and non tumor tissue (NTT) were then calculated. NTT was determined as “healthy tissue volume—tumor volume”,
For each patient, the planning volumes were well within the planning CT scans, so that the irradiated normal tissues were included in the CT volumes.
All SBRT treatment were replanned in standard 3DCRT with a 2 Gy/fraction regimen biologically equivalent to a singledose 23 Gy fraction treatment. For the present study, the total 3DCRT dose was approximated to 64 Gy, delivered as 32 × 2 Gy fraction scheme (Appendix). Finally, Equation (1) was applied to calculate the equivalent 3DCRT integral dose both for NTT and for PTV. Tumor integral dose was evaluated considering a standard α/β ratio of 10 Gy while the normalization of nontumor integral doses were calculated assuming an α/β ratio of 3 Gy. Dose normalization for OARs was performed taking into account most recent literature α/β ratio for different organs.
The choice of these values was inevitably arbitrary since the α/β concept is a nonstochastic concept referring to cell killing and at present it is not known which α/β value might be related to a stochastic effect as the induction of tumors.
Dose voxels were obtained by differential DVH. For the differential DVH to be calculated, the volumes of interest (PTV, body, OARs) are divided into a volume grid made of equalsized bins. The doses received by the single volume elements were provided straightforwardly by TPSs. Differential DVHs for NTT and PTVs are reported in
(
(
The maximum treated volume was 86.1 cm^{3} with a median volume of 33.2 cm^{3} (range between 1.5 cm^{3} and 86.1 cm^{3}). CT images were acquired with a 4D CT scanner (LightSpeed^{®} RT and Advantage 4D^{®} respiratory gating) and then registered in order to get a virtual dynamic volume which provided tumour displacements information. In all SBRT plans PTV was obtained expanding GTV (CTV = GTV) with a margin of 5–10 mm. CT slice thickness was 2.5 mm in all patients. For both techniques, OARs, PTV and Body minus PTV were then contoured by an experienced radiation oncologist. The structure “Body minus PTV” was used to calculate the overall nontumour integral dose (NTID). All the structures were contoured in such a way as not to overlap with adjacent structures (
As for SBRT treatment plans, two to five monoisocentic noncoplanar arcs were used. In one case a treatment with eight noncoplanar fixed fields was planned. For all plans, prescription was 90% of the total dose (23 Gy). On the basis of the immobilization equipment, linear margins between BrainLab’s dynamic micromultileaf collimator and PTV were chosen to be 2 mm.
The same structures were then used for 3DCRT treatment planning (TPS) with Eclipse^{®} software (Eclipse 7.3.10 Varian, Palo Alto, CA, USA). A different number of coplanar fields were used depending upon the tumor localization. All treatment plans were performed for a 6 MV Varian DBX Linac. Linear margins between multileaf collimator and PTV was 5 mm in order to have adequate target coverage. Prescription dose ranged between 94% and 96% of the therapeutic dose (edge of the PTV encompassed by 89–91% isodose curve) and all plans were optimized in order to have mean target coverage at least 95% of the prescription dose.
As for the target, the same setup uncertainties for SBRT planning were considered for 3DCRT. No margins were added for accounting ITV (Internal Target Volume) since the tumour volume was determined from 4D thoracic CT images, thus accounting for respiratory motion. CTV was obtained expanding GTV with a margin of 0.6–0.8 cm and PTV by a further expansion of 0.5–1.0 cm. A comparison between SBRT and 3DCRT treatment plans is reported in
Geometrical features and fractionation schemes of SBRT and 3DCRT plans generated with TPSs.
SBRT  3DCRT  

Margins GTV → CTV  none  0.6–0.8 cm 
Margins CTV → PTV  0.5–1.0 cm  0.5–1.5 cm 
Distance collimatorPTV  2 mm  5 mm 
Prescription dose  23 Gy × 1 fr to 90% isodose line  2 Gy × 32 fr to 94–96% isodose line 
Technique  2–5 noncoplanar arcs or 8 fixed fields  3–4 coplanar fields 
Calculation algorithm  Pencilbeam  Pencilbeam 
Collimator  microMLC  MLC 
Linac Voltage  6 MV  6 MV 
All plans were generated with commercially available treatment planning systems (TPS). 3DCRT dose calculations were performed with Eclipse^{®} implemented with pencil beam convolution algorithm and with BATHO methods for the inhomogeneity corrections. All SBRT plans were generated with BrainSCAN TPS (BrainSCAN^{TM} v.5.2.1, BrainLAB AG. Heimstetten, Germany) implemented with pencil beam algorithm and heterogeneity corrections as well.
All patients were treated with a 6 MV Varian DBX Linac since voltages below 6 MV are always recommended when irradiating tumors surrounded by lung because of the smaller penumbra widening. This recommendation is also suggested by the smaller difference found between the experimental and the predicted percentage depth doses (PDDs) inside the lung, when correctionbased algorithms are used [
The dosimetric characteristics of both linear accelerators were measured during acceptance testing and commissioning and their consistency with dose calculated by respective TPSs were verified. Measurements have shown excellent agreement between dose delivered and that calculated by both TPSs, with absolute dose difference being consistently within 1.0% for Eclipse and within 0.9% for BrainLAB TPS. Analyses were performed by using a paired twotailed Student
As a result of the hypofractionated dose delivery scheme and the higher sensitivity to fractionation of lateresponding tissues, in all SBRT plans the NTID increased compared to 3DCRT plans (
NonTumour Integral Dose (Gy × liter) and increase percentage of SBRT respect to 3DCRT. Abbreviations: ID = integral dose; 3DCRT = threedimensional conformal radiotherapy; SBRT = stereotactic body radiation therapy; EQID = integral dose normalized. Statistically significant difference were found (
Cases  NTT Volume  3DCRT  SBRT  ID 3DCRT  SBRT EQID 

(liters)  Technique  Technique  (2 Gy × 32)  (23 Gy × 1, α/β = 3Gy)  
Case 1  29.1  3 fixed fields  8 fixed fields  59.2  88.7 (+49.8%) 
Case 2  23.4  2 fixed fields  2 arcs  67.9  123.6 (+82%) 
Case 3  35.3  4 fixed fields  2 arcs  31.8  51.5 (+61.9%) 
Case 4  23.1  3 fixed fields  3 arcs  20.8  38.6 (+86%) 
Case 5  25.1  3 fixed fields  4 arcs  40.2  78.0 (+83%) 
Case 6  20.5  3 fixed fields  4 arcs  18.5  51.5 (+178%) 
Case 7  30.8  3 fixed fields  4 arcs  33.9  111.3 (+228%) 
Case 8  20.5  3 fixed fields  5 arcs  18.5  33.6 (+81%) 
PTVs integral dose (Gy × liter). As expected, no significant difference of ID to PTVs were observed (
Cases  PTV  ID 3DCRT  SBRT EQID 

Volume (cl)  (2 Gy × 32, α/β = 10 Gy)  (23 Gy × 1, α/β = 10 Gy)  
Case 1  47  3.02  2.90 
Case 2  86.1  8.21  8.58 
Case 3  12.5  0.86  0.76 
Case 4  3.9  0.25  0.25 
Case 5  14.4  0.86  0.88 
Case 6  8.8  0.56  0.40 
Case 7  23.7  1.52  1.50 
Case 8  1.5  0.10  0.11 
For each patient, EARs for the main organs of interest were calculated (
Secondary cancer risk for all solid tumors was also calculated for each patient (
As a general rule, non tumor integral dose depends on a number of factors. As reported by D’Souza [
Excess absolute cancer risk for each patient, for the OARs. EARs were calculated from DVHs according to Equation (1).
Excess absolute cancer risk for all solid tumors, for all patients.
When evaluating radiation dose to healthy tissues, especially at sites remote from the treatment region, radiation leakage may represent an important factor, increasing integral dose to normal structures. Specifically, two main sources of leakage can be considered to increase the patient NTID: transmission of radiation through the collimator leaves and leakage through the primary collimation system. It is generally believed that leakage through the leaves of a conventional collimator might carry a significant contribution to peripheral integral dose (leakage is about 2.5% for 6 MV photon beams).
More specifically, leakage radiation might play a crucial role in some special techniques. A recent work by Petti
Over the last decade integral dose has aroused a lively interest due to its alleged correlation with secondary cancers. Radiationinduced secondary malignancies are rare, but since treatment techniques improve and clinical outcomes are improving accordingly, secondary tumor risk after oncologic treatment might represent a relevant issue. Of course, the risk of secondary cancer induction from radiation treatments is likely not to be worrisome within a few years after treatment given the latency period of malignancies, but radiationinduced secondary cancer might be a relevant concern for those (especially young) patients whose progression free survival is greater than 5 years. Different works show that diseasefree survival is rapidly increasing for patients which undergo SBRT; Uematsu and
In the present paper we used a doseresponse relationship for cancer induction that includes fractionation effects, therefore suitable for radiotherapy applications. Under the assumptions made and according to the model used our study indicates that despite the fact that for all patients integral dose is higher for SBRT treatments than 3DCRT, secondary cancer risk associated to SBRT patients is significantly smaller than that calculated for 3DCRT. This suggests that integral dose may not be a good estimator for quantifying cancer induction. This is imputable to the fact that in the case of SBRT the doseresponse curve for carcinoma induction is highly nonlinear. In the present study we assumed a bellshaped behavior, consequently leading to lower cancer induction rates. Furthermore, integral dose does not consider fractionation at all, and fractionation is supposed to be directly correlated to an increased cancer risk [
It is worth noting that the results presented in this study are valid under the assumptions made: neither neutron dose nor leakage radiation accounted and risk calculations performed on the plane of interest for the treatment. In the present analysis a limitation of DVH computation might be represented by the use of Pencil Beam algorithm, which is known to have some drawbacks in low density media. Nevertheless, possible dosimetric inaccuracies are likely to affect DVH calculations (and the following DVHrelated evaluations) in both TPS in the same magnitude. Despite the use of more advanced dose evaluations algorithm is encouraged for lung treatments (anisotropic analytical algorithm and collapsed cone convolution), pencil beam algorithm is still widely used and implemented in the clinical practice both for standard 3DCRT and SBRT of lung malignancies [
Finally, some consideration about the application of the linearquadratic (LQ) model are needed. In fact, in radiotherapeutic applications, the LQ formalism is the tool most commonly used for quantitative predictions of dose/fractionations dependencies. Questions may arise when using the LQ model to describe dose response in the high dose per fraction range.
At present, the LQ model is reasonably well validated (experimentally and theoretically) and its use is reasonable up to several Grays per fraction. In addition, there is a fairly wide range of studies for which it is possible to test concordance with the LQ predictions in the 2 to 20 Gy range [
At higher doses the LQ model might have deficiencies and experimental survival curves suggest a purely linear rather than a continuation of the linearquadratic shape (continuously bending) so LQ model may not properly evaluate the tumor dose, predicting more cell kill.
Caution is advised in the presence of biomathematical model which use radiobiological parameters. In fact, although mathematical models are widely used to compare different radiotherapy technique and different fractionation scheme, the radiobiological parameters on which they are funded are still not completely optimized, thus unavoidably introducing some degree of approximation.
Our results indicate that although NTID was greater in SBRT than in 3DCRT, secondary cancer risk associated to SBRT patients is significantly smaller than that calculated for 3DCRT. This suggests that integral dose may not be a good estimator for quantifying cancer induction.
The development of reliable secondary cancer risk models seems to be a key issue in fractionated radiotherapy and comparisons of integral dose received with 3DCRT and other special techniques are strongly encouraged.
In the classic Linear Quadratic (LQ) model, the cell fraction surviving an irradiation (
Given
Thus the total biological effect
Biological Effective Dose (
Equation (A5) was used to calculate the equivalent tumour dose for a standard fractionation regimen (3DCRT), with
For the present study,
The authors declare no conflict of interest.
The authors would like to thank Uwe Schneider for his helpful suggestions. His valuable comments helped to significantly improve the manuscript.