Dosimetric comparison of 3DCRT versus IMRT in whole breast irradiation of early stage breast cancer

Purpose: The counseling regarding the treatment option is an important objective in the management of early stages breast cancer. The purpose of this study is to present a comparison between the dosimetric aspects of 3DCRT and IMRT in the whole breast radiotherapy. Methods: Both right and left sided computed tomography simulations of 14 women with early stage breast cancer were used for our retrospective study to compare the 3DCRT and IMRT. The dose prescribed was 50 Gray (Gy) in 25 fractions to the whole breast PTV. The PTV was defined by adding unequal margins to the directional safety margin status of each lumpectomy cavity (i.e., medial, lateral, superior, inferior and deep margins measured from the tumor front after the examination of the surgical specimen: 2, 1.5, and 1 cm for resection margins < 1 cm, 1-2 cm, and > 2cm, respectively) and then modified so that it was no longer closer than 3 mm to the skin surface and was no deep than the lung –chest interface. The prescribed dose delivered in 5 fractions per week schedule. Treatment plans were compared for target minimum dose, maximum dose, mean dose, conformity index, heterogeneity index and doses to organs at risk were compared and analyzed. Results: The target coverage was achieved with 90% prescription to the 95% volume of the PTV. Conformity to the PTV was significantly higher with 3DCRT technique than IMRT. 3DCRT technique seems better in sparing critical organs parameters like lung V20 and Mean, heart, V25, Maximum, both lungs V20, Mean and Dose to the Normal Healthy tissue. Conclusion: We conclude from our study that treatment technique selection for whole Breast irradiation is an important factor in sparing the adjacent normal structures and in determining the associated risk. 3DCRT produces better conformity and heterogeneity indices of the target volume, also reduces dose to OARs and reduces the risk of radiation induced heart diseases.


Introduction
An estimated 12.66 million people were diagnosed with cancer across the world in 2008, and 7.56 million people died from the disease. Just four cancer sites lung, female breast, colorectal and stomach accounted for two-fifths of the total cases diagnosed worldwide. Breast cancer is the most common cancer in females worldwide. As per World Health Organization (WHO) estimate, in Bahrain the incidence of breast cancer was 116.47 per 100,000 in 2008. Unlike other cancers, breast cancer is successfully treatable if detected at an early stage. 1 The incidence of breast cancer has increased globally over the last several decades. 2,3,4 The greatest increase has been in Asian countries. 5 In Asia, breast cancer incidence peaks among women in their forties whereas in the United States and Europe, it peaks among women in their sixties. In India premenopausal patients constitute about 50% of all patients. 6 It is expected that in the coming decades, these countries would account for majority of new breast cancer patients diagnosed globally. Over 100,000 new breast cancer patients are estimated to be diagnosed annually in India. 7 Radiotherapy is an integral part of breast cancer management after Breast Conservative Surgery (BCS) in early stage breast cancer. Survival rates are similar for BCS with adjuvant Radiotherapy (RT) and mastectomy for early stage breast cancer and Breast Conservative Surgery (BCS) is known as a gold standard. 8,9,10 Whole breast irradiation is the commonest method of management for early breast cancer treatment after BCS. The greatest challenge for radiation therapy or any cancer therapy is to attain the highest probability of cure with the least morbidity. The simplest way in theory to increase this therapeutic ratio with radiation is to encompass all cancer cells with sufficient doses of radiation during each fraction, while simultaneously sparing surrounding normal tissues. In practice, however, we have been hampered by our abilities to both identify the cancer cells and target them with radiation. The modern radiotherapy has evolved from non-site-specific techniques using bony anatomy and hand-drawn blocking toward specialized planning incorporating three-dimensional reconstructions of images and computer optimization algorithms. Corresponding to these changes, there has been specialization in the types of technology used for different cancer sites. Two-dimensional (2D) radiotherapy consisted of a single beam from one to four directions. Beam setups were usually quite simple; plans frequently consisted of opposed lateral fields or four field "boxes". Three-dimensional (3D), or Computed Tomography (CT) based, planning was a major advance because it took into account axial anatomy and complex tissue contours and while 3D planning allows for accurate dose calculations to such irregular shapes, we are still limited in the corrections we could make. The intensity-modulated radiation therapy (IMRT) allows us to modulate the intensity of each radiation beam, so each field may have one or many areas of high intensity radiation and any number of lower intensity areas within the same field, thus allowing for greater control of the dose distribution with the target. By modulating both the number of fields and the intensity of radiation within each field, we have limitless possibilities to sculpt radiation dose. Advanced treatment planning software has furthered our ability to modulate radiation dose. Instead of the clinician choosing every beam angle and weighting, computer optimization techniques can now help determine the distribution of beam intensities across a treatment volume, which often include a non-intuitive distribution of "beamlets," or 1-cm 2 areas of isointensity. 11 There are various methods to employ radiotherapy for breast cancer in women. Conventionally tangential fields are employed to treat the whole breast. With the recent advances in treatment planning technology and Multi Leaf Collimators (MLC), Three Dimensional Conformal Radiotherapy (3DCRT) is widely used for treatment of breast carcinoma. Conformal therapy reduces normal tissue doses and increases conformity to target volume. With the advent of advanced sophisticated treatment planning software intensity modulated radiation therapy is becoming increasingly popular. The aim of our study is to compare three dimensional conformal radiation therapy (3DCRT) versus intensity modulated radiation therapy (IMRT) planning based on standard plan indices using Computerized Medical Systems (CMS) Xio (4.70.02 version, ELEKTA) treatment planning system.

Methods and Materials CT Imaging
This study is conducted using treatment plans done on the Computed Tomography (CT) simulation data sets (2.5 mm slice thickness) of 14 consecutive patients (7 right sided breast carcinoma, 7 left sided breast carcinoma) with T1 or T2 axillary node negative invasive carcinoma of breast for our retrospective analysis. The Planning Tumor Volume (PTV) size varied from 855.73 cm 3 to 1347 cm 3 with a mean value of 1025.35 cm 3 . These patients were already treated with IMRT. Radiation Therapy was started within three weeks after the breast conservation surgery consisting of removal of primary tumor with a margin referred as lumpectomy or segmental mastectomy and chemotherapy. A radio opaque wire was placed around the ipsilateral breast by Radiation Oncologist to define the treatment ports for the PTV. The same CT data sets target volumes and organs at risk volumes were used for 3DCRT study.

Target and organ at risk delineation
After planning CT was done, the Digital Imaging and Communication in Medicine (DICOM) images were transferred to CMS Xio (4.70.02 version, ELEKTA) treatment planning system. The contours that were generated were the Gross Tumor Volume (GTV), Clinical Tumor Volume (CTV), Planning Target Volume (PTV), ipsilateral lung, contralateral lung, contralateral breast, heart, spinal cord and body. The GTV which is the gross tumor volume is the total lumpectomy cavity which can be identified with the help of surgical clips placed at the time of surgery. The CTV was defined by the three dimensional uniform 1.5 cm margin expanded in all directions around the GTV, however this volume was constrained to lie 5 mm within the external contour and up against the major muscle. The PTV volume was defined to lie within the radio-opaque wire kept during CT simulation as deep as the anterior chest wall muscles. The lungs and external surfaces contoured using semi-automatic contouring techniques. The CTV, PTV, and Organs at Risk (OARs) were generated in accordance with the Radiation Therapy Oncology Group (RTOG) 0319 protocol. 12

Treatment Planning Details and Dose Prescription
All treatment plans were generated with 6 MV (Mega voltage) photon beams to maintain the comparison between the two treatment techniques. Treatment plans were done using The treatment fields were almost evenly placed within an arc of 180 degree swept by the gantry. The gantry angles ranged from 300 to 160 (clockwise) for left side tumors and from 60 to 210 (counter clockwise) for right side tumors were chosen to create optimum IMRT plans. The dose prescribed to the Breast volume (PTV) was 50 Grays (Gy) in 25 fractions (2.0 Gy/fraction). The dose uniformity and conformity were calculated and evaluated.
The Conformity Index (CI) as defined in the International Commission of Radiological Units (ICRU) report 83 is The Homogeneity Index (HI) as defined in ICRU report 83 is Where, D5%, D95%, D50% is the dose received by 5%, 95%, 50% volume.

3DCRT Planning
Two opposite tangential beams were constructed to conform to whole breast PTV. A margin of 1 cm between the MLC and PTV was set for coverage. Using Beam's Eye View (BEV) fields were set up to minimize the dose to heart, left descending coronary artery (LAD), contralateral breasts and ipsilateral lung and maximize the target coverage. The "isocenter" of the treatment machine was positioned at the center of the midline joining the two parallel opposite fields. The plans were created for 3DCRT, in which tangential coplanar beams were used to produce adequate dose coverage for Planning Target Volume (PTV). Critical organs were shielded using MLC without compromising with the PTV coverage. Beam weights were adjusted until the optimum coverage and acceptable hot spots were achieved. The PTV was set to receive 95% of the prescribed dose. Also, hot spot volumes blocking subfields were determined to achieve the better dose homogeneity and to avoid the overdose in the PTV. By viewing the 105% dose cloud in a beam's eye view projection of the treatment fields, subfields were designed by blocking the volume of PTV receiving greater than 105% of the prescribed dose to boost the low dose volume of the PTV (volume of the PTV receiving less the 95% of the prescribed dose) by delivering 5 to 10 monitor units. The shape of the subfield was iteratively modified with aided visualization of 105% dose cloud in the beam's eye view. The main field and subfields were merged into one portal. In this technique, the fluence based step and shoot IMRT optimized plans were generated to achieve the same objectives described for the 3DCRT plans, the number of beam segments was not restricted during optimization and no attempts have been made for beam angle optimization as CMS Xio does not support beam angle optimization. The PTV for IMRT was the same as used for the 3DCRT plans plus an extension into the air anterior of the PTV of 1.5 cm in order to compensate the set up uncertainties and up and down movement of the chest due to respiration. The dose was prescribed to the PTV and the dose constraints presented in the Table 1 were set to the treatment planning system. Tissue heterogeneity was considered in the treatment planning optimization process and the dose calculation was done by using superposition/ convolution algorithm.

IMRT Planning
The CMS Xio (4.70.02 version, ELEKTA) treatment planning system Dose Volume Histogram (DVH) window was used to analyze the PTV's mean, maximum and minimum doses and for OAR's mean, maximum, minimum doses, percentage of volume receiving 3000cGy (V30), percentage of volume receiving 2000 cGy (V20), percentage of volume receiving 1000 cGy (V10), and isodose volumes for 50%, 30% and 10%. Also to illustrate the low dose volume effects, Dose Volume Histogram for normal healthy tissue are also incorporated and Monitor Units (MU) were also noted in order to access and understand integral dose (ID) contribution, the Monitor Units (MU) for both the plans were noted and taken for analysis. The more monitor unit signifies the more integral dose. The integral dose ID to an organ j divided into m voxels is given by the following equation :    The treatment plans were optimized to meet the planning objectives in both the treatment techniques and to achieve the prescribed dose delivery for more than 90% of the prescribed isodose to encompass greater than 95% of the PTV volume. The PTV size varied from 855.73 cm 3 to 1347 cm 3 with a mean value of 1025±35 cm 3 . In 3DCRT, 105% dose (hot spots) was observed in less than 5% of the target volume. The normalized target coverage for IMRT and 3DCRT in PTV and for both classes of the patients were presented in the Table 2a and 2b. Figure 1 demonstrates the dose distribution in axial sections for the two classes of patients (right sided diseases patient and left sided disease patient) for IMRT and 3DCRT plans of the same patient. The axial sections clearly depict the concave target PTV coverage and in all left sided breast patients, the left anterior descending coronary artery (LAD) is little away from the PTV and not receiving any significant dose in both the techniques. The comparison and dosimetric analysis for the Planning Target volume (PTV) presented in the Table 2a, 2b depicts that there is no significant difference in maximum dose and conformity index in both the treatment techniques. However, the heterogeneity index was found to be 1.16 for IMRT and 1.14 for 3DCRT (p = 0.023) in left breasts and 1.12 for IMRT and 1.10 for 3DCRT (p = 0.024) in the right breasts. All the dosimetric parameter calculated for the Planning Target Volume (PTV) except mean dose has appreciably higher values in IMRT plans than 3DCRT plans. Moreover, the dosimetric analysis carried out for ipsilateral lung dose parameters like mean dose, V5, V10 were found to have higher values in all IMRT plans than 3DCRT plans. The difference is presented in Table 3 for both classes of the patients.  Figure 6 illustrates the Dose Volume Histogram (DVH) for heart. A comparison of dosimetric parameters for heart is presented in Table 4a, 4b. These parameters show much higher values in IMRT technique than 3DCRT technique except the dose value to the 33% of the heart volume and the volume encompassed by 25% isodose line.

Discussion
Several epidemiological studies have shown that in country like India breast cancer patients usually come in advanced stage of breast cancer, breast conservative surgery is not possible, so mastectomy is the treatment of choice and early stage breast cancer is rare. In early stage breast cancer, breast conservative surgery is known as gold standard. There are distinct geometric differences between the target volume of the chest wall and the whole breast, and these differences might have an impact on the resulting dose distribution. In general, In this study tangential beam 3DCRT of the whole breast PTV is compared to IMRT. Lung Dose (MLD) below which there no Pneumonitis. 18 The clinically acceptable risk of radiation therapy depends on the risk benefit ratio of the individual patient selection.
In patients with left sided breast cancer, it is intended that the irradiated heart volume be minimized to the greatest possible degree without compromising the target coverage as the risk of pericardial events is probably related to both dose and volume of irradiation. Stewart J R et al. 19 concludes that the dose volume should be limited to 60 Gy for less than 20% of the cardiac volume and 45 Gy for more than 65% of cardiac volume. A very recent study on "Risk of Ischemic Heart Diseases in Women after Radiotherapy for Breast Cancer" by Sarah CD et al. 20 suggests that the exposure of heart to ionizing radiations during radiotherapy for breast cancer increases the subsequent rate of ischemic heart diseases. The increase is proportional to the mean dose to heart, begins within few years after exposure, and continues at least for 20 years. Woman with preexisting cardiac risk factors have greater absolute increase in risk from radiotherapy than other women. Also, the rate of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gray, with no apparent threshold. The risk starts within 5 years after radiotherapy and continuous up to the third decade after radiotherapy.
The IMRT plans contribute a modestly higher dose to adjacent healthy tissues. The main concern of with the healthy soft tissue dose increases of such magnitude is an increased risk of late secondary malignancy. 21,22 Conclusion The objective of this study was to compare the dosimetric characteristics of IMRT and 3DCRT techniques and to evaluate the characteristics of each modality when applied to the whole breast radiotherapy in the early stage of the breast cancer. The quality of the treatment plan dependence on the many factors, in general, there is an optimum plan for every patient that treats the breast tissue while sparing the organs at risk. However, the technique one may use could vary depending on the patient geometry and technology available in a radiotherapy center such as treatment planning system available, beam energy, TPS algorithm and the skills of the planner as shown by Lu 23 , Rana 24 , and Pokharel. 25 IMRT is now considered to be a mature radiotherapy technique and has become a frequently used modality in all most all the radiotherapy centers. The MLC-based IMRT technique delivers non-uniform fluences to the patient from any given position of the treatment beam to optimize the composite dose distribution and to spare the adjacent organs at risk.
We infer from this study that treatment technique selection for whole-breast irradiation is an important factor in sparing the adjacent normal structures and in determining the associated risk. 3DCRT reduces the dose to the OARs and increases the heterogeneity index on CMS Xio (4.70.02 version, ELEKTA) treatment planning system. Quantification of dose to OARs may be useful for clinicians as they counsel women with early stage breast cancer about their treatment option Moreover, according to the Sarah CD et al. 19 recent study on "Risk of Ischemic Heart Diseases in Women after Radiotherapy for Breast Cancer", the 3DCRT reduces the risk of radiation induced heart diseases by a factor of about 9.62 in right sided breast diseases than IMRT and by a factor of 1.27 in left sided breast diseases.