A prospective cohort study on postoperative radiotherapy with TomoDirect using simultaneous integrated boost technique in early breast cancer
© Lee et al.; licensee BioMed Central Ltd. 2014
Received: 29 August 2014
Accepted: 30 October 2014
Published: 19 November 2014
To evaluate the technical feasibility and toxicity of TomoDirect in breast cancer patients who received radiotherapy after breast-conserving surgery.
155 consecutive patients with breast carcinoma in situ or T1-2 breast cancer with negative lymph node received breast irradiation with TomoDirect using simultaneous integrated boost technique in the prospective cohort study. A radiation dose of 50.4 Gy and 57.4 Gy in 28 fractions was prescribed to the ipsilateral breast and tumor bed, respectively. Dosimetric parameters of target and organ at risk and acute complication were assessed prospectively.
The mean dose for the tumor bed is 58.90 Gy. The mean values of V54.53Gy (95% of the prescribed dose), V63.14Gy (110% of the prescribed dose), and V66.01Gy (115% of the prescribed dose) were 99.97%, 1.26%, and 0%, respectively. The mean value of radiation conformality index was 1.01. The mean value of radical dose homogeneity index was 0.89. The average dose irradiated to the ipsilateral lung, heart, and contralateral breast was 4.72 Gy, 1.09 Gy, and 0.19 Gy, respectively. The most common toxicity was dermatitis. During breast irradiation, grade 2 and 3 dermatitis occurred in 41 (26.5%) and 6 (3.9%) of the 155 patients, respectively. Two patients had arm lymphedema during breast irradiation. Two patients had grade 2 pneumonitis 1 month after breast irradiation.
Radiotherapy using TomoDirect in early breast cancer patients showed acceptable toxicities and optimal results in terms of target coverage and organ at risk sparing.
KeywordsBreast cancer Radiotherapy TomoTherapy Toxicity
Breast cancer is the frequently diagnosed cancer in South Korea and it accounts for about 15% of all female malignancies . The annual incidence of breast cancer has been gradually rising primarily due to increased utilization of screening mammography. Breast-conserving surgery and postoperative radiotherapy are basic treatment modalities that have been widely used to manage early breast cancer on the basis of the results of randomized prospective trials . The long-term survival rate among women who undergo breast-conserving surgery followed by breast irradiation is the same as that among women who undergo radical mastectomy.
Conventional breast radiotherapy consists of 45 to 50 Gy of whole breast irradiation performed using two tangential megavoltage photon beams and 10 to 16 Gy of boost irradiation delivered to the tumor bed with electron beams. Recently, techniques to improve the accuracy of radiation delivery to the target have advanced. Helical TomoTherapy (Accuary, Sunnyvale, CA), which can involve image-guided radiation therapy (IGRT) using a megavoltage computed tomography (CT) scan just prior to radiation treatment, is one specific example of these advancements. TomoTherapy can also yield intensity-modulated radiation therapy (IMRT) that allows for highly conformal distributions of radiation dose to the target and minimizes the irradiation to adjacent dose-limiting organs. IMRT using TomoTherapy enables the simultaneous delivery of different dose prescriptions to different target volumes in the same treatment fraction. This technique is called simultaneous integrated boost (SIB). This modality is highly effective and safe in the treatment of head and neck cancer by reducing the overall treatment time and increasing the fraction size to boost volumes .
In breast cancer patients, helical TomoTherapy is not a suitable option since the gantry continuously rotates around the patient, and this technique can deliver low-dose radiation to lungs that is associated with an occurrence of radiation pneumonitis . To avoid this inefficiency of beam usage, a TomoDirect option using static gantry positions combined with simultaneous couch translation and dynamic collimator modulation has been developed. In a pilot study, TomoDirect seemed particularly well suited for postoperative irradiation in breast cancer patients . TomoDirect achieved an optimal target volume coverage and coincident adequate normal tissue sparing in a dosimetric study .
Clinical studies of TomoDirect in breast cancer patients are scarce and have been assessed only in small and retrospective series ,. Thus, we undertook a prospective study on the technical feasibility and toxicity of TomoDirect in breast cancer patients who received postoperative radiotherapy.
166 consecutive patients with breast carcinoma in situ (pTisN0) or early breast cancer with negative axillary node (pT1-2 N0) who underwent breast-conserving surgery between January 2012 and February 2013 were included in this prospective study. They received postoperative radiotherapy with TomoDirect. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation in the Catholic University of Korea. Exclusion criteria were metastatic breast cancer, previous radiation history of chest wall due to the thoracic malignancy, and involved resection margin.
Simulation and target volume contouring
During simulation, patients were immobilized in the supine position using a foam cushion, which covered the upper body and both arms. The patient’s arms were raised above the head. A contrast-enhanced CT was scanned for the treatment plan. CT imaging ranging from cervical to lumbar vertebral body was obtained at 3-mm thicknesses and was imported to the Pinnacle3 treatment planning system (Philips Radiation Oncology Systems, Fitchburg, WI). The following structures were contoured: clinical target volume (CTV), planning target volume (PTV), and organ at risk (OAR). CTV1 is glandular tissue of the breast. CTV2 is tumor bed cavity consisting of surgical clips, postoperative change, and seroma. CTV was identified and contoured on the axial CT images. CTV was consistently expanded by 6-mm radial and craniocaudal margin to create the PTV with a constraint of reverse expansion of 4 mm to the skin surface to avoid the potential skin toxicity . Heart and lung were excluded from the PTV when needed. The PTV provided a margin around the CTV to compensate for the variability of setup during breast irradiation and motion of breast or chest with breathing. The OARs such as lung, heart, and contralateral breast were contoured. For the IMRT plan with TomoDirect, the raw dosimetric data set of each patient was transferred from the Pinnacle3 treatment planning system to the TomoTherapy Hi-Art version 4.0 planning system (Accuray, Sunnyvale, CA).
Dose prescription and constraint and planning
Endpoint and toxicity assessment
The primary endpoint of the present study was to estimate the dosimetric parameters of target coverage, homogeneity, and conformality and dose to organ at risk in breast cancer patients who received postoperative radiotherapy with TomoDirect. We also assess the fulfillment of dose constraints for PTV and OAR. Dose violation within PTV and OAR of 5.1% to 10% was considered a minor one and greater than 10% was scored as a major one . The secondary endpoint was to assess the acute complication. During the course of radiotherapy, patients were evaluated weekly to assess acute toxicities. Patients were also followed 1, 2 and 3 months after completion of radiotherapy to assess radiation toxicities. Evaluation consisted of clinical examination, complete blood counts, and chest radiography at each visit. Adverse effects of radiotherapy were assessed using the Common Terminology Criteria for Adverse Events (version 3.0). Incidence of toxicity grade ≥2 was recorded.
Written informed consent was obtained from the patient for publication of this report and any accompanying images.
Patient and treatment characteristics ( n = 155)
Axillary lymph node dissection or sentinel lymph node biopsy
Neoadjuvant or adjuvant chemotherapy
Dose distribution of the planning target volume
Dosimetric parameters for the planning target volume
Mean dose (Gy)
58.90 ± 0.43
99.97 ± 0.01
9.19 ± 2.17
1.26 ± 0.91
54.25 ± 1.77
60.87 ± 0.91
1.01 ± 0.01
0.89 ± 0.03
Average Dmin and Dmax value was 54.25 Gy and 60.87 Gy, respectively. Average rDHI value was 0.89.
Avoidance of organs at risk
Dosimetric parameters for the organ at risk
Organ at risk
Mean dose (Gy)
4.72 ± 5.16
0.93 ± 0.88
3.57 ± 1.93
5.33 ± 2.32
7.23 ± 2.95
9.42 ± 3.56
Mean dose (Gy)
1.09 ± 0.85
0.11 ± 0.36
0.31 ± 0.71
0.54 ± 1.05
0.87 ± 1.50
1.21 ± 1.84
Mean dose (Gy)
0.19 ± 0.11
0.04 ± 0.07
0.08 ± 0.13
0.17 ± 0.26
0.25 ± 0.31
0.42 ± 0.54
Early treatment toxicity
Acute treatment toxicity of breast irradiation using TomoDirect
Number (percent) of patients
Helical TomoTherapy, which enabled simultaneous IMRT and IGRT, has achieved encouraging clinical outcomes in terms of tumor response, survival, and toxicity in head and neck and prostate cancer ,. However, it is not easy to apply continuously-rotating TomoTherapy to breast cancer patients, since it is accompanied by low-dose irradiation on both lungs and can result in radiation pneumonitis .
TomoDirect, which uses static gantry positions, combined with simultaneous couch translation and multi-leaf collimator modulation makes it possible to irradiate the whole breast without low-dose radiation to lungs in breast cancer patients. The static gantry angles of TomoDirect are identical to the tangential beam angles of conventional linear accelerator. The difference between TomoDirect and conventional 3-dimensional conformal radiotherapy (3DCRT) is that the patient is stationary during breast irradiation using the conventional linear accelerator and the patient slides through the intensity-modulated beam during breast irradiation using TomoDirect. Reynders et al. assessed the dosimetric parameters of TomoDirect and 3DCRT. Compared with conventional radiotherapy, TomoDirect provided an adequate PTV coverage with a significant reduction of high-dose radiation to the OAR . In our prospective study, TomoDirect achieved perfect target dose coverage in all patients except one patient with a large breast: ≥98% of the PTV received ≥95% of the prescribed dose and ≤5% of the PTV received ≥110% of the prescribed dose. None received <115% of the prescribed dose to the PTV. The conformality of TomoDirect irradiation was good with an average RCI value of 1.01 and the homogeneity of TomoDirect irradiation was favorable with an average rDHI value of 0.89. The TomoDirect option enables specified beam angles, reducing planning time of IMRT compared with helical TomoTherapy. Moreover, the beam-on time of TomoDirect during breast irradiation is less than helical TomoTherapy and comparable to that of 3DCRT . In our study, median beam-on time was just 175 seconds. These considerations could make TomoDirect a useful option in the radiation oncology department which only equipped with helical TomoTherapy without conventional linear accelerator.
The radiation dose delivered to the organs at risk, such as the ipsilateral lung, heart, and contralateral breast, was evaluated by dosimetric values of mean dose and V10-50Gy. The incidence of moderate to severe radiation pneumonitis after radiotherapy ranges from 0% to 37% . This wide variation reflects the different types of radiotherapy and the presence or absence of neoadjuvant or adjuvant chemotherapy, which may influence the risk of radiation pneumonitis. The risk of radiation pneumonitis seems to increase as the cumulative dose of radiation to the normal lung tissue increases, and the mean lung dose and V20Gy are considered reliable dosimetric predictors for the occurrence of radiation pneumonitis . A mean lung dose <10 Gy and V20Gy <20% is associated with the radiation pneumonitis probability of <3% . In our trial, dosimetric values for the ipsilateral lung were mean dose of 4.72 Gy, V20Gy of 7.23%, and V30Gy of 5.33%, and only two patients (1.3%) had grade 2 radiation pneumonitis one month after breast irradiation using TomoDirect.
Whole breast irradiation after breast-conserving surgery is sometimes accompanied by radiation-induced heart injury. Especially, the pericardium near the tangential photon beam is a vulnerable area for radiation damage. The dose-volume relationship and mean dose for the heart is significantly associated with radiation-induced heart disease . According to the quantitative analysis of normal tissue effect in the clinic (QUANTEC) review, V25 < 10% correlates with a long-term cardiac mortality <1%, an overly safe risk estimate based on model predictions . The dose-volume relationship for pericarditis was suggested by the QUANTEC review, and predicted that mean dose <26 Gy and V30 < 46% corresponded to a pericarditis probability of <15%. In our study, mean radiation dose for the heart was just 1.09 Gy and V30 and V20 values were <1%. Thus, in our trial no patient had radiation-induced heart disease during breast irradiation and 3 months after the end of breast irradiation.
The occurrence of contralateral breast carcinoma after breast irradiation has been extensively investigated. Scattered radiation beams certainly reached the opposite breast, and this could bring about theoretical carcinogenesis on the contralateral breast. However, there was no distinct evidence that scattered radiation during breast irradiation was significantly associated with the occurrence of contralateral breast cancer. In a case–control study including a cohort of 41,109 women diagnosed with breast cancer, the risk of a second cancer in the opposite breast was significantly increased among women who underwent irradiation at a relatively young age (<45 years) . However, Fisher et al. reported that the risk for an event of contralateral breast cancer among a group treated with lumpectomy and irradiation, as compared with the total-mastectomy group, was not significantly different in the 20-year follow-up of a randomized trial . In another study, there was no statistically significant difference of the 20-year crude cumulative incidence for contralateral breast cancer between breast-conserving surgery and radiation versus mastectomy groups . In our trial, TomoDirect delivered a mean dose of 0.19 Gy to the contralateral breast and V10-50 values were all <0.5%. Thus, this scattered radiation to the contralateral breast might not be carcinogenic ,.
Although our trial showed very favorable results for target coverage and normal tissue sparing with TomoDirect in early breast cancer patients, we acknowledge that our trial had a number of limitations. First, our study should be understood in view of the inherent biases of a short-term follow-up design. We did not evaluate chronic adverse effects. Second, we did not evaluate the recurrence and survival outcome due to the short-term follow up. Thus, we do not suggest that TomoDirect using SIB in early breast cancer is as effective as conventional breast irradiation in terms of survival and recurrence. For the clear-cut assessment of long-term complication such as the occurrence of contralateral breast cancer, recurrence, and survival, a follow-up time exceeding 10 years is required.
SIB technique using TomoDirect in early breast cancer patients showed acceptable toxicity profiles and optimal results in terms of target coverage and normal tissue sparing. Survival, tumor recurrence, and concerns for the risk of contralateral breast carcinoma due to scattered radiations during breast irradiation must be evaluated through a long-term follow-up study.
JHL: idea and concept. HCL, YJS, SHK, DGK, and HJC: design and development of Study. JHL and HCL: statistical analysis. JHL and HCL: writing of manuscript and study coordinator. JHL: final revision of manuscript. All authors read and approved the final manuscript.
Hyo Chun Lee and Sung Hwan Kim equally contributed to this work. The present research has been supported by Korea Breast Cancer Foundation.
- Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS: Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat. 2014, 46: 109-123. 10.4143/crt.2014.46.2.109.PubMed CentralView ArticlePubMedGoogle Scholar
- Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong JH, Wolmark N: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002, 347: 1233-1241. 10.1056/NEJMoa022152.View ArticlePubMedGoogle Scholar
- Franceschini D, Paiar F, Meattini I, Agresti B, Pasquetti EM, Greto D, Bonomo P, Marrazzo L, Casati M, Livi L, Biti G: Simultaneous integrated boost-intensity-modulated radiotherapy in head and neck cancer. Laryngoscope. 2013, 123: E97-E103. 10.1002/lary.24257.View ArticlePubMedGoogle Scholar
- Chung Y, Yoon HI, Kim YB, Ahn SK, Keum KC, Suh CO: Radiation pneumonitis in breast cancer patients who received radiotherapy using the partially wide tangent technique after breast conserving surgery. J Breast Cancer. 2012, 15: 337-343. 10.4048/jbc.2012.15.3.337.PubMed CentralView ArticlePubMedGoogle Scholar
- Reynders T, Tournel K, De Coninck P, Heymann S, Vinh-Hung V, Van Parijs H, Duchateau M, Linthout N, Gevaert T, Verellen D, Storme G: Dosimetric assessment of static and helical TomoTherapy in the clinical implementation of breast cancer treatments. Radiother Oncol. 2009, 93: 71-79. 10.1016/j.radonc.2009.07.005.View ArticlePubMedGoogle Scholar
- Borca VC, Franco P, Catuzzo P, Migliaccio F, Zenone F, Aimonetto S, Peruzzo A, Pasquino M, Russo G, La Porta MR, Cante D, Sciacero P, Girelli G, Ricardi U, Tofani S: Does TomoDirect 3DCRT represent a suitable option for post-operative whole breast irradiation? A hypothesis-generating pilot study. Radiat Oncol 2012, 7:211.,Google Scholar
- Saibishkumar EP, MacKenzie MA, Severin D, Mihai A, Hanson J, Daly H, Fallone G, Parliament MB, Abdulkarim BS: Skin-sparing radiation using intensity-modulated radiotherapy after conservative surgery in early-stage breast cancer: a planning study. Int J Radiat Oncol Biol Phys. 2008, 2: 485-491. 10.1016/j.ijrobp.2007.06.049.View ArticleGoogle Scholar
- Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP: INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002, 20: 1167-1174. 10.1200/JCO.20.5.1167.View ArticlePubMedGoogle Scholar
- Donato V, Cianciulli M, Fouraki S, Vigna L, Rocco A, Raffetto N, Bellocchi G: Helical tomotherapy: an innovative radiotherapy technique for the treatment of locally advanced oropharynx and inoperable oral cavity carcinoma. Radiat Oncol 2013, 8:210.,Google Scholar
- Macias VA, Blanco ML, Perez-Romasanta LA: Initial experience with stereotactic body radiation therapy for localized prostate cancer using helical tomotherapy. Clin Transl Oncol. 2014, 16: 380-385. 10.1007/s12094-013-1089-y.View ArticlePubMedGoogle Scholar
- Park HJ, Kim KJ, Park SH, Kay CS, Oh JS: Early CT findings of tomotherapy-induced radiation pneumonitis after treatment of lung malignancy. Am J Roentgenol. 2009, 193: W209-W213. 10.2214/AJR.08.2298.View ArticleGoogle Scholar
- Seppenwoolde Y, Lebesque JV, de Jaeger K, Belderbos JS, Boersma LJ, Schilstra C, Henning GT, Hayman JA, Martel MK, Ten Haken RK: Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability. Int J Radiat Oncol Biol Phys. 2003, 55: 724-735. 10.1016/S0360-3016(02)03986-X.View ArticlePubMedGoogle Scholar
- Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, Bentzen SM, Nam J, Deasy JO: Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys. 2010, 76: S10-S19. 10.1016/j.ijrobp.2009.07.1754.PubMed CentralView ArticlePubMedGoogle Scholar
- Graham MV, Purdy JA, Emami B, Harms W, Bosch W, Lockett MA, Perez CA: Clinical dose volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 1999, 45: 323-329. 10.1016/S0360-3016(99)00183-2.View ArticlePubMedGoogle Scholar
- Hurkmans CW, Cho BC, Damen E, Zijp L, Mijnheer BJ: Reduction of cardiac and lung complication probabilities after breast cancer irradiation. Radiother Oncol. 2002, 62: 163-171. 10.1016/S0167-8140(01)00473-X.View ArticlePubMedGoogle Scholar
- Boice JD, Harvey EB, Blettner M, Stovall M, Flannery JT: Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med. 1992, 326: 781-785. 10.1056/NEJM199203193261201.View ArticlePubMedGoogle Scholar
- Chung MJ, Suh YJ, Lee HC, Kang DG, Kim EJ, Kim SH, Lee JH: Tumor bed volumetric changes during breast irradiation for the patients with breast cancer. Radiat Oncol J. 2013, 31: 228-233. 10.3857/roj.2013.31.4.228.PubMed CentralView ArticlePubMedGoogle Scholar
- Zucali R, Luini A, Del Vecchio M, Sacchini V, Sverzellati E, Stucchi C, Banfi A, Veronesi U: Contralateral breast cancer after limited surgery plus radiotherapy of early mammary tumors. Eur J Surg Oncol. 1987, 13: 413-417.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.