# Integral Dose and Radiation-Induced Secondary Malignancies: Comparison between Stereotactic Body Radiation Therapy and Three-Dimensional Conformal Radiotherapy

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## Abstract

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_{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 two-tailed Student t-test was performed to determine statistically significant differences between the data (p ≤ 0.05). Our study indicates that despite the fact that for all patients integral dose is higher for SBRT treatments than 3D-CRT (p = 0.002), secondary cancer risk associated to SBRT patients is significantly smaller than that calculated for 3D-CRT (p = 0.001). This suggests that integral dose is not a good estimator for quantifying cancer induction. Indeed, for the model and parameters used, hypofractionated radiotherapy has the potential for secondary cancer reduction. The development of reliable secondary cancer risk models seems to be a key issue in fractionated radiotherapy. Further assessments of integral doses received with 3D-CRT and other special techniques are also strongly encouraged.

## Acronyms

3D-CRT | Three Dimensional Conformal Radiation Therapy |

BED | Biological Effective Dose |

CTV | Clinical Target Volume |

DVH | Dose Volume Histogram |

EAR | Excess Absolute Risk |

EQID | Equivalent Integral Dose |

GTV | Gross Target Volume |

ID | Integral Dose |

IMRT | Intensity Modulated Radiation Therapy |

NTID | Normal Tissue Integral Dose |

NTT | Non Tumor Tissue |

OAR | Organ at Risk |

OED | Organ Equivalent Dose |

PTV | Planning Target Volume |

RED | Risk Equivalent Dose |

SBRT | Stereotactic Body Radiation Therapy |

TPS | Treatment Planning System |

## 1. Introduction

## 2. Materials and Methods

#### 2.1. Integral Dose Evaluation

_{kj}, D

_{kj}and ρ

_{kj}are respectively the volume, dose and density of voxel k in organ j. If the voxels have all the same size and the organ can be assumed to have a uniform density, Equation (1) can be reduced to:

^{3}was assumed for all bins.

_{1kj}and d

_{1kj}represents respectively the total dose and the fraction dose of voxel k in organ j, and α/β is the specific organ radiation sensitivity.

#### 2.2. Dose Response Relationship for Radiation Induced Second Malignancies

#### 2.3. Evaluation of the Excess Absolute Risk for Carcinoma Induction

_{org}, can be calculated as follows:

_{T}is the total organ volume and β is the slope of the dose-response curve at low dose. The quantity is also known as organ equivalent dose (OED) over the whole organ volume [28,30].

_{e}and γ

_{a}, taken from [30] and listed in Table 1.

Organ | Β * | γ_{e} | γ_{a} | α/β (Gy) | R | |
---|---|---|---|---|---|---|

3D-CRT | 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 |

_{T}is the prescribed dose to the target volume, d

_{T}is the corresponding fractionation dose and D is the absorbed dose to the organ or region of interest.

#### 2.4. Patient Selection and Treatment Planning

**Figure 1.**(

**a**) Non tumor tissue differential DVH for SBRT. (

**b**) Non tumor tissue differential DVH for 3D-CRT.

^{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 4-D 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 non-tumour integral dose (NTID). All the structures were contoured in such a way as not to overlap with adjacent structures (i.e., every voxel was assigned to only one structure).

^{®}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.

**Table 2.**Geometrical features and fractionation schemes of SBRT and 3D-CRT plans generated with TPSs.

SBRT | 3D-CRT | |
---|---|---|

Margins GTV → CTV | none | 0.6–0.8 cm |

Margins CTV → PTV | 0.5–1.0 cm | 0.5–1.5 cm |

Distance collimator-PTV | 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 |

^{®}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.

## 3. Results and Discussion

**Table 3.**Non-Tumour Integral Dose (Gy × liter) and increase percentage of SBRT respect to 3D-CRT. Abbreviations: ID = integral dose; 3D-CRT = three-dimensional conformal radiotherapy; SBRT = stereotactic body radiation therapy; EQID = integral dose normalized. Statistically significant difference were found (p = 0.002).

Cases | NTT Volume | 3D-CRT | SBRT | ID 3D-CRT | 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%) |

**Table 4.**PTVs integral dose (Gy × liter). As expected, no significant difference of ID to PTVs were observed (p = 1).

Cases | PTV | ID 3D-CRT | 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 |

**Figure 3.**Excess absolute cancer risk for each patient, for the OARs. EARs were calculated from DVHs according to Equation (1).

## 4. Conclusions

## Appendix

#### Linear Quadratic Model and BED Formalism

_{e}cell kill per Gy of the initial linear component and β is the loge cell kill per Gy

^{2}of the quadratic component of the survival curve). The α/β ratio represents the relative importance of the linear and quadratic terms. Early reacting tissues such as the skin, the intestinal epithelium, and tumours have a large α/β value of about 10 Gy, whereas late reacting tissues such as the brain and bone have a smaller α/β value of 2–3 Gy.

_{tot}is given by the product of the single surviving fractions (multiplication rule for independent events):

_{1}d

_{1}and n

_{2}d

_{2}) can be compared by equating the BEDs for the two regimens:

_{2}= 2Gy, which is biologically equivalent to a single-dose (n

_{1}= 1) fraction SBRT treatment with d

_{1}= 23Gy. If the tumour BED between 3D-CRT and SBRT is to be maintained constant, considering an α/β = 10Gy, Equation (A-6) becomes:

_{3D-CRT}was approximated to 64 Gy, delivered as 32 × 2 Gy fraction scheme.

## Conflict of Interest

## Acknowledgements

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## Share and Cite

**MDPI and ACS Style**

D'Arienzo, M.; Masciullo, S.G.; Sanctis, V.D.; Osti, M.F.; Chiacchiararelli, L.; Enrici, R.M.
Integral Dose and Radiation-Induced Secondary Malignancies: Comparison between Stereotactic Body Radiation Therapy and Three-Dimensional Conformal Radiotherapy. *Int. J. Environ. Res. Public Health* **2012**, *9*, 4223-4240.
https://doi.org/10.3390/ijerph9114223

**AMA Style**

D'Arienzo M, Masciullo SG, Sanctis VD, Osti MF, Chiacchiararelli L, Enrici RM.
Integral Dose and Radiation-Induced Secondary Malignancies: Comparison between Stereotactic Body Radiation Therapy and Three-Dimensional Conformal Radiotherapy. *International Journal of Environmental Research and Public Health*. 2012; 9(11):4223-4240.
https://doi.org/10.3390/ijerph9114223

**Chicago/Turabian Style**

D'Arienzo, Marco, Stefano G. Masciullo, Vitaliana De Sanctis, Mattia F. Osti, Laura Chiacchiararelli, and Riccardo M. Enrici.
2012. "Integral Dose and Radiation-Induced Secondary Malignancies: Comparison between Stereotactic Body Radiation Therapy and Three-Dimensional Conformal Radiotherapy" *International Journal of Environmental Research and Public Health* 9, no. 11: 4223-4240.
https://doi.org/10.3390/ijerph9114223