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Comparison of IORT (Radical and Boost Dose) and EBRT in Terms of Disease-Free Survival and Overall Survival according to Demographic, Pathologic, and Biological Factors in Patients with Breast Cancer

Comparison of IORT (Radical and Boost Dose) and EBRT in Terms of Disease-Free Survival and... Hindawi International Journal of Surgical Oncology Volume 2021, Article ID 2476527, 9 pages https://doi.org/10.1155/2021/2476527 Research Article Comparison of IORT (Radical and Boost Dose) and EBRT in Terms of Disease-Free Survival and Overall Survival according to Demographic, Pathologic, and Biological Factors in Patients with Breast Cancer 1,2 2,3 2 Solmaz Hashemi , Seyedmohammadreza Javadi , Mohammad Esmaeil Akbari , 4 5 Hamidreza Mirzaei , and Seied Rabi Mahdavi Tabriz University of Medical Sciences, General Surgery Department, Tabriz, Iran Cancer Research Center Shahid Beheshti, University of Medical Sciences, Tehran, Iran Hamadan University of Medical Sciences, General Surgery Department, Hamadan, Iran Shahid Beheshti University of Medical Sciences, Cancer Research Center, Tehran, Iran Department of Medical Physics, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran Correspondence should be addressed to Mohammad Esmaeil Akbari; profmeakbari@gmail.com Received 17 May 2020; Revised 31 March 2021; Accepted 7 April 2021; Published 16 April 2021 Academic Editor: Gaetano Gallo Copyright © 2021 Solmaz Hashemi et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. )e standard treatment for breast cancer is breast-conserving surgery (BCS) with radiotherapy. If external beam radiation therapy (EBRT) can be safely replaced with intraoperative radiotherapy (IORT), it will help patients to save their breast and to have equivocal or better results in DFS and overall survival (OS). Methods. A total of 2022 patients with breast cancer treated during 6 years were enrolled in the current study. A total of 657, 376, and 989 patients received EBRT, radical, and boost dose by IORT, respectively, according to the IRIORT consensus protocol. )e primary endpoint was recurrence and death. )e secondary endpoint was the role of variables in recurrence and death. Results. With a mean follow-up of 34.5 and 40.18 months for the IORT and EBRT groups, respectively, there was a significant difference in DFS between electron boost and X-ray boost groups (P � 0.037) and the electron radical group compared with EBRT (P � 0.025), but there was no significant difference between other boost and radical groups in DFS and OS. Conclusions. IORT can be a preferred treatment modality because of its noninferior outcomes, and in some special conditions, it has superior outcomes compared to EBRT, particularly in delivering radical dose with IORT. shown that preserving the breast can save the lives of patients 1. Background with breast cancer [5]. Radiotherapy in BCS is of high th In the 19 century, breast cancer was treated by invasive importance for obtaining the ideal results in terms of re- surgical approach, which was described by Halstead as a currence and survival [6–8]. Radiotherapy can eradicate radical mastectomy [1]. With the introduction of breast- residual tumor cells by single- or double-stranded breakage conserving surgery (BCS), this method, along with radio- of DNA and creation of free radicals [9]. Patients receiving therapy, came to be considered as the standard in breast external whole-breast radiotherapy (WBRT) received cancer surgery. During this time, various studies with more 45–50 Gy of radiation in 25 fractions over 5-6 weeks, fol- than 20 years of follow-up showed no difference in treatment lowed by a booster of 10 Gy in 5 fractions. Because of the outcomes between BCS with radiotherapy and modified length of radiotherapy, some patients eschew BCS and prefer radical mastectomy [2–4]. Even in recent studies, it has been mastectomy [10]. Furthermore, radiation can damage 2 International Journal of Surgical Oncology Table 1: IRIORT consensus protocol for radical dose. adjacent organs such as the lungs and heart, and acute and chronic complications such as erythema, burns, skin Patients’ factors Suitable Possible Contraindicated dryness, fibrosis, fat necrosis, and telangiectasia can Age 50≤ 45–50 <45 occur [11]. Tumor size ≤3 3–3.5 ≥3.5 Intraoperative radiotherapy (IORT) is an accelerated Margins Negative Negative Positive partial breast irradiation (APBI) technique delivered at the Grade 1 and 2 Any — time of lumpectomy. It has manifold advantages such as LVI Negative Any Positive giving radiation therapy to the well-vascularized and oxy- ER status Positive Any — genated bed of tumor, the limitation of tumor cell repo- Multicentricity No No Yes Multifocality No Yes — pulations, reduction in cytokine production, giving a IDC Yes Yes — minimum dose of radiation to adjacent organs, and patient ILC Yes Yes — convenience [12]. In 2009, the American Society of Radia- Pure DCIS ≤3 cm 3-4 cm >4 cm tion Oncology (ASTRO) consensus published a guideline for EIC <25% ≥25% Diffuse APBI and recommended three categories (suitable, cau- Her2 Any — — tionary, and unsuitable) for patient selection. Ki67 <30% ≥30% — In a randomized noninferiority trial, Vaidya et al. Nodal status Negative Negative (i−, i+) Positive compared IORT (20–50 kV) with WBI (40–56 Gy± boost). Axillary surgery SLNB SLNB, ALND — Two-thirds of patients received IORT at the time of Neoadjuvant Not Not allowed If used lumpectomy (prepathology group) and one-third received treatment allowed IORT after the preparation of the pathology report (post- LVI, lymphovascular invasion; EIC, extensive in situ component; SLNB, pathology group). At 29 months of follow-up, TARGIT-A sentinel lymph node biopsy; ALND, axillary lymph node dissection; ILC, invasive lobular carcinoma; DCIS, ductal carcinoma in situ. had a higher rate of local recurrence in the IORTgroup (3.3% vs. 1.3%; P � 0.04). Local recurrence was significantly dif- ferent in the postpathology group (5.4% vs. 1.7%; P � 0.07), the removal of the tumor. IOERT was performed, using but not in the prepathology group (2.1% vs. 1.1% P � 0.3), LIAC (light intraoperative accelerator), a mobile linear and there was no difference in overall survival (OS) [13]. accelerated delivering energy levels of the electron Veronesi et al. compared IORT (21 Gy-6–9 MeV) with (6–12 MeV). )e patients categorized as suitable and WBI (50 Gy/25 fractions + 10 Gy boost). A 21 Gy with possible groups in the IRIORT consensus received 6–9 MeV electron was delivered to 1305 women aged 48–75 21 Gy as a radical dose; otherwise, they would receive years old with a tumor size of ≤ 2.5 cm. With a mean follow- 12 Gy as a boost dose by making flaps in breast tissue up of 5.8 years, local recurrence had a higher rate (4.4% vs. around the tumor cavity with a maximum thickness of 0.4%; P< 0.0001), and there was no difference in survival 2 cm. )e protection of the chest wall was achieved (96.8% vs. 96.9%) [14]. using lead discs. Supplemental EBRT was delivered for In this study, we delivered IORT with both X-ray and patients who received the boost dose. )e second group electrons and divided each group into radical and boost dose was divided in this way into 2 subgroups of electron subgroups according to the IRIORT (Islamic Republic radical (21 Gy) and electron boost (12 Gy). intraoperative radiotherapy) consensus. )en, we compared )e third group: after doing BCS for 375 patients and the efficacy of this modality with the control group that the assurance of margin status in the frozen section, received WBRT. 20 Gy intraoperative X-ray radiation therapy (IOXRT) of 50 kV was delivered to breast tissue around the 2. Materials and Methods tumor cavity. IOXRT was performed using INTRA- BEAM ZEISS. If demographic, pathologic, and bio- A total of 2022 patients with breast cancer treated with BCS logical characteristics of the tumor, according to in three centers under the supervision of the Cancer Re- IRIORT (Islamic Republic intraoperative radiother- search Center of the Shahid Beheshti University of Medical apy), were in suitable and possible groups, IORT would Sciences (Tehran, Iran) were enrolled between September be mentioned as a radical dose and the patients would 2013 and September 2019. In each center, the technique of continue therapy by chemotherapy and hormone radiotherapy was different. )e eligibility of patients to therapy. Otherwise, a boost dose would be used and the receive the radical or boost dose of IORT was determined by patient would need supplemental EBRT. )e third patients’ demographic, pathologic, and biological factors group was divided into subgroups of X-ray radical and according to the IRIORT consensus (Table 1). X-ray boost. )e patients were divided into the following groups: Patients with invasive breast cancer would be excluded )e first group: BCS was performed for 657 patients. from the study if they had metastatic disease, refused )ey received 45–50 Gy external beam radiation treatment, or did not continue the treatment. Patients were therapy (EBRT) in 25 fractions for 5-6 weeks and then visited by the surgeon and radiooncologist every six months 10 Gy boost dose in 5 fractions. for up to two years. Next, mammography was performed )e second group: intraoperative electron radiation yearly one year after the surgery and then every two years. If therapy (IOERT) was delivered to 1075 patients after the interval visit time of every patient exceeded more than International Journal of Surgical Oncology 3 one year, telephone contact would be initiated to determine Table 3 presents factors associated with recurrence the last situation of the patients. among patients that received a boost dose of IORT. Patients receiving a boost dose of radiotherapy by IORT, Disease-free survival (DFS) was defined as the time from diagnosis to the occurrence of recurrence (as local recur- stage, tumor size, grade, and hormone receptors had a rence or distant metastasis in two groups of bone metastasis significant difference in the increase of local recurrence risk and other organ metastasis). OS was defined as the time from (Table 3). diagnosis to the last follow-up of the patient or the time of In the univariate analysis, there was a lower recurrence death. rate in stages 1 and 2 in comparison with stage 3 (HR: 0.32, Overall, 2022 patients were enrolled in this study, 657 95% CI: 0.15–0.66, and HR: 0.42, 95% CI: 0.28–0.64; of whom were assigned to the control group and received P � 0.002), grade 2 tumors in comparison with grade 3 EBRT. A total of 1021 patients received IOERT, 706 of tumors (HR: 0.57, 95% CI: 0.38–0.86; P � 0.008), hormone whom received the boost dose and 315 who received the receptor positive tumors in comparison with hormone re- radical dose. Of 344 patients who received IOXRT, 283 ceptor negative tumors (HR: 0.61, 95% CI: 0.38–0.97; P � 0.04), and tumor size of ≤2.5 cm in comparison with a received the boost dose and 61 received the radical dose. Patients in the X-ray radical and electron radical groups tumor size of >3 cm (HR: 0.58, 95% CI: 0.36–0.92; were compared with stages 1 and 2 of the control group, P � 0.021). In the multivariate analysis of these variables, and patients in the X-ray boost and electron boost groups grade 2 tumors had a lower recurrence rate with 44% HR in were compared with stages 1, 2, and 3 of the control comparison with grade 3 tumors (P � 0.038). )e 5-year group. DFS for EBRT, electron boost, and X-ray boost groups was )e present longitudinal nonrandomized cohort study 91.3%, 92.3%, and 89.5%, respectively. )ere was no sig- compared the recurrence and survival of the electron radical nificant difference between electron boost and EBRT and X-ray radical groups with the EBRT group and the (P � 0.26) and between X-ray boost and EBRT (P � 0.36). electron boost and X-ray boost groups with the EBRTgroup. However, there was a significant difference between electron )e primary endpoints were recurrence (local and dis- boost and X-ray boost groups (P � 0.037), and the electron boost group had a better DFS (Figure 1). tant) and death. )e secondary endpoints were the role of age, tumor size, positive lymph nodes, grade, LVI, HR, Her2, )e 5-year OS in EBRT, electron boost, and X-ray boost and ki67 factors in recurrence and death. groups was 95.1%, 97.5%, and 97.2%, respectively. In terms Cumulative hazard function and survival plots were of OS, there was no significant difference between the drawn using the Kaplan–Meier method. )e log-rank test electron boost group and the EBRT (P � 0.048), X-ray boost was used to evaluate the survival difference between the two and EBRT (P � 0.58) group, and the electron boost and treatment radiotherapy groups, as well. Hazard ratios (HRs) X-ray boost group (P � 0.58) (Figure 2). of the variables in DFS and OS were evaluated using a In the univariate analysis, death showed a significant univariate Cox proportional hazards regression model. Only difference in stage 3 compared with stages 1 and 2 (HR: 0.32, variables that were significant in levels 0 and 1 were eval- 95% CI: 0.11–0.96, and HR: 0.23, 95% CI: 0.11–0.47; uated with multivariate Cox proportional hazards regres- P � 0.043), but had no significant difference in the multi- sion. SPSS was used to analyze the data. variate analysis. A total of 376 patients received a radical dose of IORT, 315 and 61 of who were in electron radical and X-ray 3. Results radical groups, respectively. Table 4 presents the char- acteristics of patients and tumors in the EBRT and IORT As mentioned above, 989 patients received the boost dose of IORT, 706 and 283 of who were in the electron boost and groups. X-ray boost groups, respectively. Local recurrence occurred in 1.9% (10 patients), 1% (3 Table 2 presents the characteristics of patients and tu- patients), and 1.6% (1 patient) of the patients of the EBRT, mors in the EBRT and IORT groups. electron radical, and X-ray radical groups, respectively. )ere was no significant difference in these groups. Bone Local recurrence occurred in 2.7% (18 patients), 2.4% (17 patients), and 2.1% (6 patients) of the patients of the EBRT, metastasis was 1.9% (10 patients), 0%, and 1.6% (1 patient) in the EBRT, electron radical, and X-ray radical groups, re- electron boost, and X-ray boost groups, respectively. )ere was no significant difference among these groups. Bone spectively. Bone metastasis did not occur in the electron radical group. metastasis constituted 2.3% (15 patients), 0.8% (6 patients), and 3.5% (10 patients) of the EBRT, electron boost, and Other distant organ metastasis was 2.3% (12 patients), 1% (3 patients), and 2.3% (2 patients) in the EBRT, electron X-ray boost groups, respectively. Bone metastasis occurred less in the group that received the electron boost. Other radical, and X-ray radical groups, respectively. Also, there distant organ metastasis was 3.7% (24 patients), 2.8% (20 was a lower rate of other organ metastasis in the electron patients), and 3.5% (10 patients) in the EBRT, electron boost, radical group. Death occurred in 1.4% (7 patients), 0.6% (2 and X-ray boost groups, respectively. Death occurred in patients), and 1.6% (1 patient) of the patients of the EBRT, electron radical, and X-ray radical groups, respectively. A 2.9% (19 patients), 2% (14 patients), and 2.1% (6 patients) in the EBRT, electron boost, and X-ray boost groups, re- lower death rate occurred in the electron radical group. Table 5 presents the factors associated with recurrence spectively. Concerning death, there was no significant dif- ference in these groups. among patients who received a radical dose of IORT. 4 International Journal of Surgical Oncology Table 2: Clinical, pathologic, and treatment-related characteristics of the EBRT and boost-IORT groups. EBRT Electron boost X-ray -boost Total % N % N % N % 657 100 706 100 283 100 1646 100 Stage 1 89 13.50 132 19 30 10.60 251 24.70 2 428 65.10 430 61.80 168 59.40 1026 57.40 3 140 21.30 134 19.30 85 30 359 17.90 Total 657 100 696 100 283 100 1636 100 Size ≤2.5 cm 312 53.10 374 58.30 115 42.40 801 60.00 2.5 � 3 cm 144 24.50 99 15.40 39 14.40 282 17.00 >3 cm 132 22.40 169 26.30 117 43.20 418 23.10 Total 588 100 642 100 271 100 1501 100 Grade 1 54 8.60 47 7.00 31 12.30 132 10.30 2 336 53.40 379 56.80 97 38.30 812 53.50 3 239 38 241 36.10 125 49.40 605 36.20 Total 629 100 667 100 253 100 1549 100 LVI Positive 254 42 328 49.90 118 72.40 700 43.00 Negative 351 58 329 50.10 45 27.60 725 57.00 Total 605 100 657 100 163 100 1425 100 Ki67 >30% 32 11.80 176 29.00 23 35.90 231 27.10 ≤30% 239 88.20 431 71.00 41 64.10 711 72.90 Total 271 100 607 100 64 100 942 100 ER Positive 372 76.40 517 72.30 175 72.30 1064 77.30 Negative 115 23.60 158 27.70 67 27.70 340 22.70 Total 487 100 675 100 242 100 1404 100 HER2 Positive 91 23.80 89 14.00 68 25.50 248 19.10 Negative 292 76.20 547 86.00 199 74.50 1038 80.90 Total 383 100 636 100 267 100 1286 100 Age <40 160 24.90 135 20.90 88 31.10 383 19.80 �40–50 193 30.00 236 36.50 100 35.30 529 31.90 ≥50 290 45.10 275 42.60 95 33.60 660 48.30 Total 643 100 646 100 283 100 1572 100 Histology IDC 591 90.90 449 64.50 161 62.60 1201 74.90 ILC 25 3.80 83 11.90 35 13.60 143 8.90 IDC + DCIS 23 3.50 93 13.40 39 15.20 155 9.70 IDC + ILC 2 0.30 60 8.60 19 7.40 81 5.10 Others 9 1.40 11 1.60 3 1.20 23 1.40 Adjuvant therapy CT + HT 245 68.40 435 72.00 166 70.00 846 70.60 HT alone 33 9.20 19 3.10 6 2.50 58 4.80 CT alone 80 22.30 150 24.80 65 27.40 295 24.60 Total 358 100 604 100 237 100 1199 100 In a univariate analysis of variables in patients receiving )ere was a significant difference in DFS between the a radical dose of radiotherapy by IORT, tumor size (HR: electron radical group and EBRT (P � 0.025), but there was 0.38, 95% CI: 0.16–0.90; P � 0.029) and electron beam (HR: no significant difference between the X-ray radical group 0.37, 95% CI: 0.15–0.91; P � 0.031) had a significant dif- and EBRT (P � 0.92) and the electron radical and X-ray ference in the increase of local recurrence risk, but there was radical groups (P � 0.07) (Figure 3). no significant difference in the multivariate analysis. )e 5- )e 5-year OS in EBRT, electron radical, and X-ray year DFS of EBRT, electron radical, and X-ray radical groups radical groups was 97.3%, 98.9%, and 96.8%, respectively. was 93.5%, 96.7%, and 91.9%, respectively. In terms of OS, there was no significant difference between International Journal of Surgical Oncology 5 Table 3: Factors associated with recurrence in patients that received boost dose by IORT (P value was considered concerning each variable that has the most risk). Electron boost X-ray boost P value N % N % 1 7/125 5.30 0/30 0.00 0.002 Stage 2 18/412 4.20 9/159 5.40 — 3 12/122 9.00 12/73 14.10 ≤2.5 cm 14/360 3.70 6/109 5.20 0.021 Size 2.5 � 3 cm 6/93 6.10 1/38 2.60 0.96 >3 cm 14/155 8.30 12/105 10.30 1 2/45 4.30 2/29 6.50 0.12 Grade 2 14/365 3.70 4/93 4.10 0.008 3 19/222 7.90 13/112 10.40 Positive 18/310 5.50 11/107 9.30 0.4 LVI Negative 18/311 5.50 3/42 6.70 >30% 8/168 4.50 0/23 0.00 0.37 KI67 ≤30% 24/407 5.60 2/39 4.90 Positive 5/84 5.60 5/63 7.40 0.85 HER2 Negative 29/518 5.30 15/184 7.50 Positive 25/492 4.80 10/165 5.70 ER Negative 10/148 6.30 10/57 14.90 0.04 Positive 19/431 4.20 0/0 0.00 PR Negative 9/159 5.40 0/0 0.00 0.19 <40 7/128 5.20 6/82 6.80 0.09 Age �40–50 14/222 5.90 10/90 10.00 0.56 ≥50 12/263 4.40 5/90 5.30 Survival functions Survival functions 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0.000 20.000 40.000 60.000 80.000 0.000 20.000 40.000 60.000 80.000 Time_to_recurrence Time_to_death Group Group EBRT EBRT-censored EBRT EBRT-censored Electron_boost Electron_boost-censored Electron_boost Electron_boost-censored X-ray_boost X-ray_boost-censored X-ray_boost X-ray_boost-censored Figure 1: Cumulative incidence of disease-free survival in the Figure 2: Cumulative incidence of overall survival in boost groups boost groups in comparison with EBRT. in comparison with EBRT. the electron radical group and EBRT (P � 0.15), the X-ray 4. Discussion radical group and EBRT (P � 0.63), and the electron radical group and the X-ray radical group (P � 0.051) (Figure 4). IORT not only has a noninferior outcome in comparison In the univariate analysis of variables, there was a sig- with EBRT but also has a superior outcome under nificant difference in OS in patients with hormone receptor other conditions. In the present study, IORT, as a positive in comparison with hormone receptor negative boost dose, does not show a significant difference with patients (HR: 0.25, 95% CI: 0.07–0.88; P � 0.032). But, there EBRT in terms of DFS and OS. However, stage, tumor was no significant difference in the multivariate analysis. size, grade, and hormone receptors of the tumor showed Cum survival Cum survival 6 International Journal of Surgical Oncology Table 4: Clinical, pathologic, and treatment-related characteristics of the EBRT and radical-IORT groups. EBRT Electron radical X-ray radical Total N % N % N % N % 517 100 315 100 61 100 893 100 Stage 1 89 17.20 222 70.90 24 40.00 335 37.60 2 428 82.80 91 29.10 36 60.00 555 62.40 Total 517 100 313 100 60 100 890 100 Size ≤2.5 cm 237 52.70 276 88.20 46 78.00 559 68.00 2.5 � 3 cm 83 18.40 25 8.00 11 18.60 119 14.50 >3 cm 130 28.90 12 3.80 2 3.40 144 17.50 Total 450 100 313 100 59 100 822 100 Grade 1 46 9.30 50 16.80 15 26.30 111 13.10 2 261 52.70 181 60.70 25 43.90 467 54.90 3 188 38.00 67 22.50 17 29.80 272 32.00 Total 495 100 298 100 57 100 850 100 LVI Positive 188 39.70 35 11.90 10 76.90 233 29.80 Negative 286 60.30 260 88.10 3 23.10 549 70.20 Total 474 100 295 100 13 100 782 100 Ki67 >30% 27 12.20 101 36.50 0 0.00 128 25.40 ≤30% 195 87.80 176 63.50 4 100.00 375 74.60 Total 222 100 277 100 4 100 503 100 ER Positive 372 76.40 256 83.90 39 81.30 667 79.40 Negative 115 23.60 49 16.10 9 18.80 173 20.60 Total 487 100 305 100 48 100 840 100 HER2 Positive 91 23.80 52 18.30 11 19.30 154 21.30 Negative 292 76.20 232 81.70 46 80.70 570 78.70 Total 383 100 284 100 57 100 724 100 Age <40 110 21.90 3 1.00 0 0.00 113 12.90 �40–50 166 33.00 72 22.90 19 31.70 257 29.30 ≥50 227 45.10 239 76.10 41 68.30 507 57.80 Total 503 100 314 100 60 100 877 100 Histology IDC 483 94.50 218 70.10 39 79.60 740 85.00 ILC 20 3.90 53 17.00 5 10.20 78 9.00 IDC + DCIS 0 0.00 19 6.10 0 0.00 19 2.20 IDC + ILC 0 0.00 17 5.50 5 10.20 22 2.50 Others 8 1.60 4 1.30 0 0.00 12 1.40 Adjuvant therapy CT + HT 245 68.40 117 51.10 26 65.00 388 61.90 HT alone 33 9.20 78 34.10 7 17.50 118 18.80 CT alone 80 22.30 34 14.80 7 17.50 121 19.30 Total 358 100.00 229 100.00 40 100.00 627 100.00 a significant difference in the increase of local recurrence cytokine production that affects the tissue microenvironment risk. and immune system [16]. Relative biological effectiveness is a In an analysis conducted in our center on locally advanced change in tissue microenvironment that is not favorable to patients after neoadjuvant chemotherapy, in the IORT of invasion or tumor growth. patients with the photon in comparison with the electron as a A single large dose of radiotherapy causes an immune boost dose and EBRT, the rate of events was lower, although response that regresses tumor growth in areas that are not there was no significant difference [15]. )e biological effects irradiated or in distant metastasis. Mole called it the of IORT consist of single- and double-stranded breakage of “abscopal effect” in 1953 as the antitumor effect of radio- DNA, limitation of tumor cell repopulations, and reduction in therapy in a site other than the primary site of the tumor International Journal of Surgical Oncology 7 Table 5: Factors associated with recurrence in patients that received radical dose by IORT (P value was considered concerning each variable that has the most risk). Electron radical X-ray radical P value N % N % 1 4/218 1.80 2/22 8.30 Stage 0.08 2 2/89 2.20 135 2.80 ≤2.5 cm 5/271 1.80 2/44 4.30 Size 0.02 2.5 � 3 cm 1/24 4.00 1/10 9.10 1 1/49 2.00 0/15 0.00 0.15 Grade 2 3/178 1.70 2/23 8.00 0.71 3 2/65 3.00 1/16 5.90 Positive 1/34 2.90 0/10 0.00 LVI 0.58 Negative 5/255 1.90 0/3 0.00 >30% 4/97 4.00 0/0 0.00 Ki67 0.95 ≤30% 2/174 1.10 0/4 0.00 Positive 0/52 0.00 0/11 0.00 HER2 0.4 Negative 6/226 2.60 3/43 6.50 Positive 5/251 2.00 0/39 0.00 ER 0.25 Negative 1/48 2.00 1/8 11.10 Positive 5/223 2.20 0/0 0.00 PR 0.14 Negative 1/58 1.70 0/0 0.00 Survival functions Survival functions 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0.000 20.000 40.000 60.000 80.000 0.000 20.000 40.000 60.000 80.000 Time_to_recurrence Time_to_death Group Group EBRT EBRT-censored EBRT EBRT-censored Electron_radical Electron_radical-censored Electron_radical Electron_radical-censored X-ray_radical X-ray_radical-censored X-ray_radical X-ray_radical-censored Figure 3: Cumulative incidence of disease-free survival in the Figure 4: Cumulative incidence of overall survival in the radical radical groups in comparison with EBRT. groups in comparison with EBRT. [17, 18]. )us, IORT acts like a vaccine that stimulates the who received 10 Gy electrons as the boost dose. With six immune system and protects the patient against cancer. years of follow-up, the local recurrence rate was 0.8% [21]. We conducted a study in the cancer research center on Vaidya et al. enrolled 299 patients to receive 20 Gy 50 kV 968 patients with breast cancer (IDC and ILC) to compare X-ray as boost dose like the TARGIT method. At 60.5 months of follow-up, the locoregional recurrence rate was IOERT (a boost dose) with EBRT. )e findings suggested that IOERT was noninferior in comparison with EBRT 1.7% [22]. So, it seems that giving a boost dose of radio- (P � 0.215) [19]. therapy by IORT is an acceptable method. Multiple studies evaluated IORT when it was used as the In the present study, DFS in patients, who received boost dose. One was Chang’s study, which enrolled 55 IOERT as a radical dose, had a significant statistical dif- patients to receive 5 Gy 50 kV X-rays. At a mean follow-up of ference with EBRT (P � 0.025), but not in the IOXRT group 3.3 years, they had no local recurrence [20]. and the univariate analysis of variables; tumor size had a )ese findings of this study were in line with a study significant difference in the increase of local recurrence risk carried out by Fitedastner et al., who enrolled 1109 patients (P � 0.029). OS showed no significant difference in groups Cum survival Cum survival 8 International Journal of Surgical Oncology [2] B. Fisher, S. Anderson, J. Bryant et al., “Twenty-year follow-up that received a radical dose of IORT in comparison with the of a randomized trial comparing total mastectomy, lump- EBRTgroup; however, hormone receptors of tumor caused a ectomy, and lumpectomy plus irradiation for the treatment of significant difference in the OS (P � 0.032), which was not invasive breast cancer,” New England Journal of Medicine, established by multivariate analysis. vol. 347, no. 16, pp. 1233–1241, 2002. TARGIT-A and ELIOT trials were based on 50 Gy low [3] U. Veronesi, N. Cascinelli, L. Mariani et al., “Twenty-year kV energy and high-voltage electron beam, respectively. follow-up of a randomized study comparing breast-con- )ey evaluated local recurrence in comparison with EBRT. serving surgery with radical mastectomy for early breast Local recurrence rate for TARGIT-A and ELIOT was 3.3 vs. cancer,” New England Journal of Medicine, vol. 347, no. 16, 1.3% (P � 0.3) and 4.4% vs. 0.4% (P< 0.0001) [20], re- pp. 1227–1232, 2002. spectively [13, 14]. [4] S. Litiere, ` G. Werutsky, I. S. Fentiman et al., “Breast con- In a recent study, 1153 patients received delayed targeted serving therapy versus mastectomy for stage I-II breast cancer: IORT, and local recurrence and survival were compared 20 year follow-up of the EORTC 10801 phase 3 randomised trial,” /e Lancet Oncology, vol. 13, no. 4, pp. 412–419, 2012. with EBRT. Patients were younger than 45 years old with a [5] M. E. Akbari, M. Khayamzadeh, H. R. Mirzaei et al., “Saving tumor size of ≤3.5 cm. With a mean follow-up of 9 years, the breast saves the lives of breast cancer patients,” Inter- there was no statistically significant difference in local re- national Journal of Surgical Oncology, vol. 2020, Article ID currence-free survival (P � 0.57), mastectomy-free survival 8709231, 8 pages, 2020. (P � 0.38), distant DFS (P � 0.98), and OS (P � 0.3) [23]. [6] B. Fisher, J. Bryant, J. J. Dignam et al., “Tamoxifen, radiation In another study conducted in our center, we compared therapy, or both for prevention of ipsilateral breast tumor local recurrence in IOERT as a radical dose with EBRT, and recurrence after lumpectomy in women with invasive breast there was no significant recurrence between groups cancers of one centimeter or less,” Journal of Clinical On- (P � 0.335) [24]. Montpelier delivered 21 Gy IOERT for 42 cology, vol. 20, pp. 4141–4149, 2001. patients between 2004 and 2007. With 6 years of follow-up, [7] S. Darby, P. McGale, C. Correa et al., “Effect of radiotherapy local recurrence was 9.5% [25]. A different approach to after breast-conserving surgery on 10 year recurrence and 15 radiotherapy by doing IORT may thus be indicated. year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomized trials,” Lancet, vol. 378, pp. 1707–1716, 2011. 5. Conclusions [8] K. S. Hughes, L. A. Schnaper, J. R. Bellon et al., “Lumpectomy plus tamoxifen with or without irradiation in women age 70 IORT can be a preferred treatment modality to WBRT years or older with early breast cancer: long-term follow-up of because of its noninferior outcomes, and in some conditions, CALGB 9343,” Journal of Clinical Oncology, vol. 31, no. 19, using better patient selection for delivering a radical dose by pp. 2382–2387, 2013. IORT, it has superior outcomes compared to EBRT. Patient [9] J. A. Reisz, N. Bansal, J. Qian, W. Zhao, and C. M. Furdui, convenience is one advantage of IORT, in which the patient “Effects of ionizing radiation on biological molecules- does not spend a great deal of time in radiotherapy centers mechanisms of damage and emerging methods of detection,” for a long time, and it protects the patient from EBRT Antioxidants & Redox Signaling, vol. 21, no. 2, pp. 260–292, complications. 2014. [10] W. F. Athas, M. Adams-Cameron, W. C. Hunt, A. Amir-Fazli, We could expand our descriptions for patient selection and C. R. Key, “Travel distance to radiation therapy and in the IORT groups and deliver IORT even to younger receipt of radiotherapy following breast-conserving surgery,” patients, larger tumor sizes, and other histologies, such as JNCI: Journal of the National Cancer Institute, vol. 92, no. 3, ILC and DCIS. We could develop IORT usage for in-breast pp. 269–271, 2000. tumor recurrences and use BCS with IORT in these cases. [11] S. F. Shaitelman, P. J. Schlembach, I. Arzu et al., “Acute and )e era of PBI has represented a paradigm shift in the short-term toxic effects of conventionally fractionated vs treatment of early-stage breast cancer similar to that of the hypofractionated whole-breast irradiation,” JAMA Oncology, introduction of BCS as an alternative to mastectomy. vol. 1, no. 7, pp. 931–941, 2015. [12] F. Sedlmayer, H. B. K. Rahim, H. Dieter Kogelnik et al., “Quality assurance in breast cancer brachytherapy: geographic miss in Data Availability the interstitial boost treatment of the tumor bed,” International Journal of Radiation Oncology∗Biology∗Physics, vol. 34, no. 5, )e data used to support the findings of this study are pp. 1133–1139, 1996. available from the corresponding author upon request. [13] J. S. Vaidya, M. Baum, J. S. Tobias et al., “Targeted intra- operative radiotherapy (targit): an innovative method of Conflicts of Interest treatment for early breast cancer,” Annals of Oncology, vol. 12, no. 8, pp. 1075–1080, 2001. )e authors declare that they have no conflicts of interest. [14] U. Veronesi, R. Orecchia, P. Maisonneuve et al., “Intra- operative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence References trial,” /e Lancet Oncology, vol. 14, no. 13, pp. 1269–1277, [1] W. S. Halsted, “)e results of operation for the cure of cancer of the breast performed at the Johns Hopkins hospital from [15] N. Moini, N. Nafissi, M. E. Akbari et al., “Compairing the June, 1889, to January 1894,” Annals of Surgery, vol. 20, outcome of intraoperative radiotherapy with electron pp. 497–555, 1984. (IOERT) and low-kV X-ray (IOXRT) and external beam International Journal of Surgical Oncology 9 radiotherapy (EBRT) in breast cancer after neoadjuvant chemotherapy,” International Journal of Cancer Management, vol. 12, no. 8, Article ID e94547, 2019. [16] B. Belletti, J. S. Vaidya, S. D’Andrea et al., “Targeted intra- operative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding,” Clinical Cancer Research, vol. 14, no. 5, pp. 1325–1332, 2008. [17] N. Brix, A. Tiefenthaller, H. Anders, C. Belka, and K. Lauber, “Abscopal, immunological effects of radiotherapy: narrowing the gap between clinical and preclinical experiences,” Im- munological Reviews, vol. 280, no. 1, pp. 249–279, 2017. [18] R. H. Mole, “Whole body irradiation-radiobiology or medi- cine?” /e British Journal of Radiology, vol. 26, no. 305, pp. 234–241, 1953. [19] H. Moayeri, M. E. Akbari, S. R. Mahdavi, H. R. Mirzaei, A. Salati et al., “Outcomes of breast cancer (invasive lobular and ductal carcinoma) treated with boost intraoperative electron radiotherapy versus conventional external beam radiotherapy,” International Journal of Cancer Management, vol. 12, no. 1, Article ID e84850, 2019. [20] D. W. Chang, L. te Marvelde, and B. H. Chua, “Prospective study of local control and late radiation toxicity after intra- operative radiation therapy boost for early breast cancer,” International Journal of Radiation Oncology∗Biology∗Physics, vol. 88, no. 1, pp. 73–79, 2014. [21] G. Fitedastner, F. Sedlmayer, F. Mertz et al., “IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer. long term results of an ISIORT pooled analysis,” Radiation Oncology, vol. 108, pp. 279–286, [22] J. S. Vaidya, M. Baum, J. S. Tobias et al., “Long-Term results of targeted intraoperative radiotherapy (targit) boost during breast-conserving surgery,” International Journal of Radiation Oncology Biology Physics, vol. 81, no. 4, pp. 1091–1097, 2011. [23] J. S. Vaidya, M. Bulsara, C. Saunders et al., “Effect of delayed targeted intraoperative radiotherapy vs whole-breast radio- therapy on local recurrence and survival long-term results from the TARGIT-a randomized clinical trial in early breast cancer,” JAMA Oncology, vol. 6, no. 7, Article ID e200249, [24] A. Salati, M. E. Akbari, N. Nafisi et al., “Comparing outcome of radical dose intraoperative radiotherapy with electron (IOERT) according to IRIORT consensus and external beam radiotherapy in early breast cancer,” International Journal of Cancer Management, vol. 11, no. 3, pp. 63–69, 2019. [25] C. Lemanski, D. Azria, S. Gourgou-Bourgade et al., “Electrons for intraoperative radiotherapy in selected breast-cancer patients: late results of the Montpellier phase II trial,” Ra- diation Oncology, vol. 8, no. 1, p. 191, 2013. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Surgical Oncology Hindawi Publishing Corporation

Comparison of IORT (Radical and Boost Dose) and EBRT in Terms of Disease-Free Survival and Overall Survival according to Demographic, Pathologic, and Biological Factors in Patients with Breast Cancer

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Copyright © 2021 Solmaz Hashemi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi International Journal of Surgical Oncology Volume 2021, Article ID 2476527, 9 pages https://doi.org/10.1155/2021/2476527 Research Article Comparison of IORT (Radical and Boost Dose) and EBRT in Terms of Disease-Free Survival and Overall Survival according to Demographic, Pathologic, and Biological Factors in Patients with Breast Cancer 1,2 2,3 2 Solmaz Hashemi , Seyedmohammadreza Javadi , Mohammad Esmaeil Akbari , 4 5 Hamidreza Mirzaei , and Seied Rabi Mahdavi Tabriz University of Medical Sciences, General Surgery Department, Tabriz, Iran Cancer Research Center Shahid Beheshti, University of Medical Sciences, Tehran, Iran Hamadan University of Medical Sciences, General Surgery Department, Hamadan, Iran Shahid Beheshti University of Medical Sciences, Cancer Research Center, Tehran, Iran Department of Medical Physics, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran Correspondence should be addressed to Mohammad Esmaeil Akbari; profmeakbari@gmail.com Received 17 May 2020; Revised 31 March 2021; Accepted 7 April 2021; Published 16 April 2021 Academic Editor: Gaetano Gallo Copyright © 2021 Solmaz Hashemi et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. )e standard treatment for breast cancer is breast-conserving surgery (BCS) with radiotherapy. If external beam radiation therapy (EBRT) can be safely replaced with intraoperative radiotherapy (IORT), it will help patients to save their breast and to have equivocal or better results in DFS and overall survival (OS). Methods. A total of 2022 patients with breast cancer treated during 6 years were enrolled in the current study. A total of 657, 376, and 989 patients received EBRT, radical, and boost dose by IORT, respectively, according to the IRIORT consensus protocol. )e primary endpoint was recurrence and death. )e secondary endpoint was the role of variables in recurrence and death. Results. With a mean follow-up of 34.5 and 40.18 months for the IORT and EBRT groups, respectively, there was a significant difference in DFS between electron boost and X-ray boost groups (P � 0.037) and the electron radical group compared with EBRT (P � 0.025), but there was no significant difference between other boost and radical groups in DFS and OS. Conclusions. IORT can be a preferred treatment modality because of its noninferior outcomes, and in some special conditions, it has superior outcomes compared to EBRT, particularly in delivering radical dose with IORT. shown that preserving the breast can save the lives of patients 1. Background with breast cancer [5]. Radiotherapy in BCS is of high th In the 19 century, breast cancer was treated by invasive importance for obtaining the ideal results in terms of re- surgical approach, which was described by Halstead as a currence and survival [6–8]. Radiotherapy can eradicate radical mastectomy [1]. With the introduction of breast- residual tumor cells by single- or double-stranded breakage conserving surgery (BCS), this method, along with radio- of DNA and creation of free radicals [9]. Patients receiving therapy, came to be considered as the standard in breast external whole-breast radiotherapy (WBRT) received cancer surgery. During this time, various studies with more 45–50 Gy of radiation in 25 fractions over 5-6 weeks, fol- than 20 years of follow-up showed no difference in treatment lowed by a booster of 10 Gy in 5 fractions. Because of the outcomes between BCS with radiotherapy and modified length of radiotherapy, some patients eschew BCS and prefer radical mastectomy [2–4]. Even in recent studies, it has been mastectomy [10]. Furthermore, radiation can damage 2 International Journal of Surgical Oncology Table 1: IRIORT consensus protocol for radical dose. adjacent organs such as the lungs and heart, and acute and chronic complications such as erythema, burns, skin Patients’ factors Suitable Possible Contraindicated dryness, fibrosis, fat necrosis, and telangiectasia can Age 50≤ 45–50 <45 occur [11]. Tumor size ≤3 3–3.5 ≥3.5 Intraoperative radiotherapy (IORT) is an accelerated Margins Negative Negative Positive partial breast irradiation (APBI) technique delivered at the Grade 1 and 2 Any — time of lumpectomy. It has manifold advantages such as LVI Negative Any Positive giving radiation therapy to the well-vascularized and oxy- ER status Positive Any — genated bed of tumor, the limitation of tumor cell repo- Multicentricity No No Yes Multifocality No Yes — pulations, reduction in cytokine production, giving a IDC Yes Yes — minimum dose of radiation to adjacent organs, and patient ILC Yes Yes — convenience [12]. In 2009, the American Society of Radia- Pure DCIS ≤3 cm 3-4 cm >4 cm tion Oncology (ASTRO) consensus published a guideline for EIC <25% ≥25% Diffuse APBI and recommended three categories (suitable, cau- Her2 Any — — tionary, and unsuitable) for patient selection. Ki67 <30% ≥30% — In a randomized noninferiority trial, Vaidya et al. Nodal status Negative Negative (i−, i+) Positive compared IORT (20–50 kV) with WBI (40–56 Gy± boost). Axillary surgery SLNB SLNB, ALND — Two-thirds of patients received IORT at the time of Neoadjuvant Not Not allowed If used lumpectomy (prepathology group) and one-third received treatment allowed IORT after the preparation of the pathology report (post- LVI, lymphovascular invasion; EIC, extensive in situ component; SLNB, pathology group). At 29 months of follow-up, TARGIT-A sentinel lymph node biopsy; ALND, axillary lymph node dissection; ILC, invasive lobular carcinoma; DCIS, ductal carcinoma in situ. had a higher rate of local recurrence in the IORTgroup (3.3% vs. 1.3%; P � 0.04). Local recurrence was significantly dif- ferent in the postpathology group (5.4% vs. 1.7%; P � 0.07), the removal of the tumor. IOERT was performed, using but not in the prepathology group (2.1% vs. 1.1% P � 0.3), LIAC (light intraoperative accelerator), a mobile linear and there was no difference in overall survival (OS) [13]. accelerated delivering energy levels of the electron Veronesi et al. compared IORT (21 Gy-6–9 MeV) with (6–12 MeV). )e patients categorized as suitable and WBI (50 Gy/25 fractions + 10 Gy boost). A 21 Gy with possible groups in the IRIORT consensus received 6–9 MeV electron was delivered to 1305 women aged 48–75 21 Gy as a radical dose; otherwise, they would receive years old with a tumor size of ≤ 2.5 cm. With a mean follow- 12 Gy as a boost dose by making flaps in breast tissue up of 5.8 years, local recurrence had a higher rate (4.4% vs. around the tumor cavity with a maximum thickness of 0.4%; P< 0.0001), and there was no difference in survival 2 cm. )e protection of the chest wall was achieved (96.8% vs. 96.9%) [14]. using lead discs. Supplemental EBRT was delivered for In this study, we delivered IORT with both X-ray and patients who received the boost dose. )e second group electrons and divided each group into radical and boost dose was divided in this way into 2 subgroups of electron subgroups according to the IRIORT (Islamic Republic radical (21 Gy) and electron boost (12 Gy). intraoperative radiotherapy) consensus. )en, we compared )e third group: after doing BCS for 375 patients and the efficacy of this modality with the control group that the assurance of margin status in the frozen section, received WBRT. 20 Gy intraoperative X-ray radiation therapy (IOXRT) of 50 kV was delivered to breast tissue around the 2. Materials and Methods tumor cavity. IOXRT was performed using INTRA- BEAM ZEISS. If demographic, pathologic, and bio- A total of 2022 patients with breast cancer treated with BCS logical characteristics of the tumor, according to in three centers under the supervision of the Cancer Re- IRIORT (Islamic Republic intraoperative radiother- search Center of the Shahid Beheshti University of Medical apy), were in suitable and possible groups, IORT would Sciences (Tehran, Iran) were enrolled between September be mentioned as a radical dose and the patients would 2013 and September 2019. In each center, the technique of continue therapy by chemotherapy and hormone radiotherapy was different. )e eligibility of patients to therapy. Otherwise, a boost dose would be used and the receive the radical or boost dose of IORT was determined by patient would need supplemental EBRT. )e third patients’ demographic, pathologic, and biological factors group was divided into subgroups of X-ray radical and according to the IRIORT consensus (Table 1). X-ray boost. )e patients were divided into the following groups: Patients with invasive breast cancer would be excluded )e first group: BCS was performed for 657 patients. from the study if they had metastatic disease, refused )ey received 45–50 Gy external beam radiation treatment, or did not continue the treatment. Patients were therapy (EBRT) in 25 fractions for 5-6 weeks and then visited by the surgeon and radiooncologist every six months 10 Gy boost dose in 5 fractions. for up to two years. Next, mammography was performed )e second group: intraoperative electron radiation yearly one year after the surgery and then every two years. If therapy (IOERT) was delivered to 1075 patients after the interval visit time of every patient exceeded more than International Journal of Surgical Oncology 3 one year, telephone contact would be initiated to determine Table 3 presents factors associated with recurrence the last situation of the patients. among patients that received a boost dose of IORT. Patients receiving a boost dose of radiotherapy by IORT, Disease-free survival (DFS) was defined as the time from diagnosis to the occurrence of recurrence (as local recur- stage, tumor size, grade, and hormone receptors had a rence or distant metastasis in two groups of bone metastasis significant difference in the increase of local recurrence risk and other organ metastasis). OS was defined as the time from (Table 3). diagnosis to the last follow-up of the patient or the time of In the univariate analysis, there was a lower recurrence death. rate in stages 1 and 2 in comparison with stage 3 (HR: 0.32, Overall, 2022 patients were enrolled in this study, 657 95% CI: 0.15–0.66, and HR: 0.42, 95% CI: 0.28–0.64; of whom were assigned to the control group and received P � 0.002), grade 2 tumors in comparison with grade 3 EBRT. A total of 1021 patients received IOERT, 706 of tumors (HR: 0.57, 95% CI: 0.38–0.86; P � 0.008), hormone whom received the boost dose and 315 who received the receptor positive tumors in comparison with hormone re- radical dose. Of 344 patients who received IOXRT, 283 ceptor negative tumors (HR: 0.61, 95% CI: 0.38–0.97; P � 0.04), and tumor size of ≤2.5 cm in comparison with a received the boost dose and 61 received the radical dose. Patients in the X-ray radical and electron radical groups tumor size of >3 cm (HR: 0.58, 95% CI: 0.36–0.92; were compared with stages 1 and 2 of the control group, P � 0.021). In the multivariate analysis of these variables, and patients in the X-ray boost and electron boost groups grade 2 tumors had a lower recurrence rate with 44% HR in were compared with stages 1, 2, and 3 of the control comparison with grade 3 tumors (P � 0.038). )e 5-year group. DFS for EBRT, electron boost, and X-ray boost groups was )e present longitudinal nonrandomized cohort study 91.3%, 92.3%, and 89.5%, respectively. )ere was no sig- compared the recurrence and survival of the electron radical nificant difference between electron boost and EBRT and X-ray radical groups with the EBRT group and the (P � 0.26) and between X-ray boost and EBRT (P � 0.36). electron boost and X-ray boost groups with the EBRTgroup. However, there was a significant difference between electron )e primary endpoints were recurrence (local and dis- boost and X-ray boost groups (P � 0.037), and the electron boost group had a better DFS (Figure 1). tant) and death. )e secondary endpoints were the role of age, tumor size, positive lymph nodes, grade, LVI, HR, Her2, )e 5-year OS in EBRT, electron boost, and X-ray boost and ki67 factors in recurrence and death. groups was 95.1%, 97.5%, and 97.2%, respectively. In terms Cumulative hazard function and survival plots were of OS, there was no significant difference between the drawn using the Kaplan–Meier method. )e log-rank test electron boost group and the EBRT (P � 0.048), X-ray boost was used to evaluate the survival difference between the two and EBRT (P � 0.58) group, and the electron boost and treatment radiotherapy groups, as well. Hazard ratios (HRs) X-ray boost group (P � 0.58) (Figure 2). of the variables in DFS and OS were evaluated using a In the univariate analysis, death showed a significant univariate Cox proportional hazards regression model. Only difference in stage 3 compared with stages 1 and 2 (HR: 0.32, variables that were significant in levels 0 and 1 were eval- 95% CI: 0.11–0.96, and HR: 0.23, 95% CI: 0.11–0.47; uated with multivariate Cox proportional hazards regres- P � 0.043), but had no significant difference in the multi- sion. SPSS was used to analyze the data. variate analysis. A total of 376 patients received a radical dose of IORT, 315 and 61 of who were in electron radical and X-ray 3. Results radical groups, respectively. Table 4 presents the char- acteristics of patients and tumors in the EBRT and IORT As mentioned above, 989 patients received the boost dose of IORT, 706 and 283 of who were in the electron boost and groups. X-ray boost groups, respectively. Local recurrence occurred in 1.9% (10 patients), 1% (3 Table 2 presents the characteristics of patients and tu- patients), and 1.6% (1 patient) of the patients of the EBRT, mors in the EBRT and IORT groups. electron radical, and X-ray radical groups, respectively. )ere was no significant difference in these groups. Bone Local recurrence occurred in 2.7% (18 patients), 2.4% (17 patients), and 2.1% (6 patients) of the patients of the EBRT, metastasis was 1.9% (10 patients), 0%, and 1.6% (1 patient) in the EBRT, electron radical, and X-ray radical groups, re- electron boost, and X-ray boost groups, respectively. )ere was no significant difference among these groups. Bone spectively. Bone metastasis did not occur in the electron radical group. metastasis constituted 2.3% (15 patients), 0.8% (6 patients), and 3.5% (10 patients) of the EBRT, electron boost, and Other distant organ metastasis was 2.3% (12 patients), 1% (3 patients), and 2.3% (2 patients) in the EBRT, electron X-ray boost groups, respectively. Bone metastasis occurred less in the group that received the electron boost. Other radical, and X-ray radical groups, respectively. Also, there distant organ metastasis was 3.7% (24 patients), 2.8% (20 was a lower rate of other organ metastasis in the electron patients), and 3.5% (10 patients) in the EBRT, electron boost, radical group. Death occurred in 1.4% (7 patients), 0.6% (2 and X-ray boost groups, respectively. Death occurred in patients), and 1.6% (1 patient) of the patients of the EBRT, electron radical, and X-ray radical groups, respectively. A 2.9% (19 patients), 2% (14 patients), and 2.1% (6 patients) in the EBRT, electron boost, and X-ray boost groups, re- lower death rate occurred in the electron radical group. Table 5 presents the factors associated with recurrence spectively. Concerning death, there was no significant dif- ference in these groups. among patients who received a radical dose of IORT. 4 International Journal of Surgical Oncology Table 2: Clinical, pathologic, and treatment-related characteristics of the EBRT and boost-IORT groups. EBRT Electron boost X-ray -boost Total % N % N % N % 657 100 706 100 283 100 1646 100 Stage 1 89 13.50 132 19 30 10.60 251 24.70 2 428 65.10 430 61.80 168 59.40 1026 57.40 3 140 21.30 134 19.30 85 30 359 17.90 Total 657 100 696 100 283 100 1636 100 Size ≤2.5 cm 312 53.10 374 58.30 115 42.40 801 60.00 2.5 � 3 cm 144 24.50 99 15.40 39 14.40 282 17.00 >3 cm 132 22.40 169 26.30 117 43.20 418 23.10 Total 588 100 642 100 271 100 1501 100 Grade 1 54 8.60 47 7.00 31 12.30 132 10.30 2 336 53.40 379 56.80 97 38.30 812 53.50 3 239 38 241 36.10 125 49.40 605 36.20 Total 629 100 667 100 253 100 1549 100 LVI Positive 254 42 328 49.90 118 72.40 700 43.00 Negative 351 58 329 50.10 45 27.60 725 57.00 Total 605 100 657 100 163 100 1425 100 Ki67 >30% 32 11.80 176 29.00 23 35.90 231 27.10 ≤30% 239 88.20 431 71.00 41 64.10 711 72.90 Total 271 100 607 100 64 100 942 100 ER Positive 372 76.40 517 72.30 175 72.30 1064 77.30 Negative 115 23.60 158 27.70 67 27.70 340 22.70 Total 487 100 675 100 242 100 1404 100 HER2 Positive 91 23.80 89 14.00 68 25.50 248 19.10 Negative 292 76.20 547 86.00 199 74.50 1038 80.90 Total 383 100 636 100 267 100 1286 100 Age <40 160 24.90 135 20.90 88 31.10 383 19.80 �40–50 193 30.00 236 36.50 100 35.30 529 31.90 ≥50 290 45.10 275 42.60 95 33.60 660 48.30 Total 643 100 646 100 283 100 1572 100 Histology IDC 591 90.90 449 64.50 161 62.60 1201 74.90 ILC 25 3.80 83 11.90 35 13.60 143 8.90 IDC + DCIS 23 3.50 93 13.40 39 15.20 155 9.70 IDC + ILC 2 0.30 60 8.60 19 7.40 81 5.10 Others 9 1.40 11 1.60 3 1.20 23 1.40 Adjuvant therapy CT + HT 245 68.40 435 72.00 166 70.00 846 70.60 HT alone 33 9.20 19 3.10 6 2.50 58 4.80 CT alone 80 22.30 150 24.80 65 27.40 295 24.60 Total 358 100 604 100 237 100 1199 100 In a univariate analysis of variables in patients receiving )ere was a significant difference in DFS between the a radical dose of radiotherapy by IORT, tumor size (HR: electron radical group and EBRT (P � 0.025), but there was 0.38, 95% CI: 0.16–0.90; P � 0.029) and electron beam (HR: no significant difference between the X-ray radical group 0.37, 95% CI: 0.15–0.91; P � 0.031) had a significant dif- and EBRT (P � 0.92) and the electron radical and X-ray ference in the increase of local recurrence risk, but there was radical groups (P � 0.07) (Figure 3). no significant difference in the multivariate analysis. )e 5- )e 5-year OS in EBRT, electron radical, and X-ray year DFS of EBRT, electron radical, and X-ray radical groups radical groups was 97.3%, 98.9%, and 96.8%, respectively. was 93.5%, 96.7%, and 91.9%, respectively. In terms of OS, there was no significant difference between International Journal of Surgical Oncology 5 Table 3: Factors associated with recurrence in patients that received boost dose by IORT (P value was considered concerning each variable that has the most risk). Electron boost X-ray boost P value N % N % 1 7/125 5.30 0/30 0.00 0.002 Stage 2 18/412 4.20 9/159 5.40 — 3 12/122 9.00 12/73 14.10 ≤2.5 cm 14/360 3.70 6/109 5.20 0.021 Size 2.5 � 3 cm 6/93 6.10 1/38 2.60 0.96 >3 cm 14/155 8.30 12/105 10.30 1 2/45 4.30 2/29 6.50 0.12 Grade 2 14/365 3.70 4/93 4.10 0.008 3 19/222 7.90 13/112 10.40 Positive 18/310 5.50 11/107 9.30 0.4 LVI Negative 18/311 5.50 3/42 6.70 >30% 8/168 4.50 0/23 0.00 0.37 KI67 ≤30% 24/407 5.60 2/39 4.90 Positive 5/84 5.60 5/63 7.40 0.85 HER2 Negative 29/518 5.30 15/184 7.50 Positive 25/492 4.80 10/165 5.70 ER Negative 10/148 6.30 10/57 14.90 0.04 Positive 19/431 4.20 0/0 0.00 PR Negative 9/159 5.40 0/0 0.00 0.19 <40 7/128 5.20 6/82 6.80 0.09 Age �40–50 14/222 5.90 10/90 10.00 0.56 ≥50 12/263 4.40 5/90 5.30 Survival functions Survival functions 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0.000 20.000 40.000 60.000 80.000 0.000 20.000 40.000 60.000 80.000 Time_to_recurrence Time_to_death Group Group EBRT EBRT-censored EBRT EBRT-censored Electron_boost Electron_boost-censored Electron_boost Electron_boost-censored X-ray_boost X-ray_boost-censored X-ray_boost X-ray_boost-censored Figure 1: Cumulative incidence of disease-free survival in the Figure 2: Cumulative incidence of overall survival in boost groups boost groups in comparison with EBRT. in comparison with EBRT. the electron radical group and EBRT (P � 0.15), the X-ray 4. Discussion radical group and EBRT (P � 0.63), and the electron radical group and the X-ray radical group (P � 0.051) (Figure 4). IORT not only has a noninferior outcome in comparison In the univariate analysis of variables, there was a sig- with EBRT but also has a superior outcome under nificant difference in OS in patients with hormone receptor other conditions. In the present study, IORT, as a positive in comparison with hormone receptor negative boost dose, does not show a significant difference with patients (HR: 0.25, 95% CI: 0.07–0.88; P � 0.032). But, there EBRT in terms of DFS and OS. However, stage, tumor was no significant difference in the multivariate analysis. size, grade, and hormone receptors of the tumor showed Cum survival Cum survival 6 International Journal of Surgical Oncology Table 4: Clinical, pathologic, and treatment-related characteristics of the EBRT and radical-IORT groups. EBRT Electron radical X-ray radical Total N % N % N % N % 517 100 315 100 61 100 893 100 Stage 1 89 17.20 222 70.90 24 40.00 335 37.60 2 428 82.80 91 29.10 36 60.00 555 62.40 Total 517 100 313 100 60 100 890 100 Size ≤2.5 cm 237 52.70 276 88.20 46 78.00 559 68.00 2.5 � 3 cm 83 18.40 25 8.00 11 18.60 119 14.50 >3 cm 130 28.90 12 3.80 2 3.40 144 17.50 Total 450 100 313 100 59 100 822 100 Grade 1 46 9.30 50 16.80 15 26.30 111 13.10 2 261 52.70 181 60.70 25 43.90 467 54.90 3 188 38.00 67 22.50 17 29.80 272 32.00 Total 495 100 298 100 57 100 850 100 LVI Positive 188 39.70 35 11.90 10 76.90 233 29.80 Negative 286 60.30 260 88.10 3 23.10 549 70.20 Total 474 100 295 100 13 100 782 100 Ki67 >30% 27 12.20 101 36.50 0 0.00 128 25.40 ≤30% 195 87.80 176 63.50 4 100.00 375 74.60 Total 222 100 277 100 4 100 503 100 ER Positive 372 76.40 256 83.90 39 81.30 667 79.40 Negative 115 23.60 49 16.10 9 18.80 173 20.60 Total 487 100 305 100 48 100 840 100 HER2 Positive 91 23.80 52 18.30 11 19.30 154 21.30 Negative 292 76.20 232 81.70 46 80.70 570 78.70 Total 383 100 284 100 57 100 724 100 Age <40 110 21.90 3 1.00 0 0.00 113 12.90 �40–50 166 33.00 72 22.90 19 31.70 257 29.30 ≥50 227 45.10 239 76.10 41 68.30 507 57.80 Total 503 100 314 100 60 100 877 100 Histology IDC 483 94.50 218 70.10 39 79.60 740 85.00 ILC 20 3.90 53 17.00 5 10.20 78 9.00 IDC + DCIS 0 0.00 19 6.10 0 0.00 19 2.20 IDC + ILC 0 0.00 17 5.50 5 10.20 22 2.50 Others 8 1.60 4 1.30 0 0.00 12 1.40 Adjuvant therapy CT + HT 245 68.40 117 51.10 26 65.00 388 61.90 HT alone 33 9.20 78 34.10 7 17.50 118 18.80 CT alone 80 22.30 34 14.80 7 17.50 121 19.30 Total 358 100.00 229 100.00 40 100.00 627 100.00 a significant difference in the increase of local recurrence cytokine production that affects the tissue microenvironment risk. and immune system [16]. Relative biological effectiveness is a In an analysis conducted in our center on locally advanced change in tissue microenvironment that is not favorable to patients after neoadjuvant chemotherapy, in the IORT of invasion or tumor growth. patients with the photon in comparison with the electron as a A single large dose of radiotherapy causes an immune boost dose and EBRT, the rate of events was lower, although response that regresses tumor growth in areas that are not there was no significant difference [15]. )e biological effects irradiated or in distant metastasis. Mole called it the of IORT consist of single- and double-stranded breakage of “abscopal effect” in 1953 as the antitumor effect of radio- DNA, limitation of tumor cell repopulations, and reduction in therapy in a site other than the primary site of the tumor International Journal of Surgical Oncology 7 Table 5: Factors associated with recurrence in patients that received radical dose by IORT (P value was considered concerning each variable that has the most risk). Electron radical X-ray radical P value N % N % 1 4/218 1.80 2/22 8.30 Stage 0.08 2 2/89 2.20 135 2.80 ≤2.5 cm 5/271 1.80 2/44 4.30 Size 0.02 2.5 � 3 cm 1/24 4.00 1/10 9.10 1 1/49 2.00 0/15 0.00 0.15 Grade 2 3/178 1.70 2/23 8.00 0.71 3 2/65 3.00 1/16 5.90 Positive 1/34 2.90 0/10 0.00 LVI 0.58 Negative 5/255 1.90 0/3 0.00 >30% 4/97 4.00 0/0 0.00 Ki67 0.95 ≤30% 2/174 1.10 0/4 0.00 Positive 0/52 0.00 0/11 0.00 HER2 0.4 Negative 6/226 2.60 3/43 6.50 Positive 5/251 2.00 0/39 0.00 ER 0.25 Negative 1/48 2.00 1/8 11.10 Positive 5/223 2.20 0/0 0.00 PR 0.14 Negative 1/58 1.70 0/0 0.00 Survival functions Survival functions 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0.000 20.000 40.000 60.000 80.000 0.000 20.000 40.000 60.000 80.000 Time_to_recurrence Time_to_death Group Group EBRT EBRT-censored EBRT EBRT-censored Electron_radical Electron_radical-censored Electron_radical Electron_radical-censored X-ray_radical X-ray_radical-censored X-ray_radical X-ray_radical-censored Figure 3: Cumulative incidence of disease-free survival in the Figure 4: Cumulative incidence of overall survival in the radical radical groups in comparison with EBRT. groups in comparison with EBRT. [17, 18]. )us, IORT acts like a vaccine that stimulates the who received 10 Gy electrons as the boost dose. With six immune system and protects the patient against cancer. years of follow-up, the local recurrence rate was 0.8% [21]. We conducted a study in the cancer research center on Vaidya et al. enrolled 299 patients to receive 20 Gy 50 kV 968 patients with breast cancer (IDC and ILC) to compare X-ray as boost dose like the TARGIT method. At 60.5 months of follow-up, the locoregional recurrence rate was IOERT (a boost dose) with EBRT. )e findings suggested that IOERT was noninferior in comparison with EBRT 1.7% [22]. So, it seems that giving a boost dose of radio- (P � 0.215) [19]. therapy by IORT is an acceptable method. Multiple studies evaluated IORT when it was used as the In the present study, DFS in patients, who received boost dose. One was Chang’s study, which enrolled 55 IOERT as a radical dose, had a significant statistical dif- patients to receive 5 Gy 50 kV X-rays. At a mean follow-up of ference with EBRT (P � 0.025), but not in the IOXRT group 3.3 years, they had no local recurrence [20]. and the univariate analysis of variables; tumor size had a )ese findings of this study were in line with a study significant difference in the increase of local recurrence risk carried out by Fitedastner et al., who enrolled 1109 patients (P � 0.029). OS showed no significant difference in groups Cum survival Cum survival 8 International Journal of Surgical Oncology [2] B. Fisher, S. Anderson, J. Bryant et al., “Twenty-year follow-up that received a radical dose of IORT in comparison with the of a randomized trial comparing total mastectomy, lump- EBRTgroup; however, hormone receptors of tumor caused a ectomy, and lumpectomy plus irradiation for the treatment of significant difference in the OS (P � 0.032), which was not invasive breast cancer,” New England Journal of Medicine, established by multivariate analysis. vol. 347, no. 16, pp. 1233–1241, 2002. TARGIT-A and ELIOT trials were based on 50 Gy low [3] U. Veronesi, N. Cascinelli, L. Mariani et al., “Twenty-year kV energy and high-voltage electron beam, respectively. follow-up of a randomized study comparing breast-con- )ey evaluated local recurrence in comparison with EBRT. serving surgery with radical mastectomy for early breast Local recurrence rate for TARGIT-A and ELIOT was 3.3 vs. cancer,” New England Journal of Medicine, vol. 347, no. 16, 1.3% (P � 0.3) and 4.4% vs. 0.4% (P< 0.0001) [20], re- pp. 1227–1232, 2002. spectively [13, 14]. [4] S. Litiere, ` G. Werutsky, I. S. Fentiman et al., “Breast con- In a recent study, 1153 patients received delayed targeted serving therapy versus mastectomy for stage I-II breast cancer: IORT, and local recurrence and survival were compared 20 year follow-up of the EORTC 10801 phase 3 randomised trial,” /e Lancet Oncology, vol. 13, no. 4, pp. 412–419, 2012. with EBRT. Patients were younger than 45 years old with a [5] M. E. Akbari, M. Khayamzadeh, H. R. Mirzaei et al., “Saving tumor size of ≤3.5 cm. With a mean follow-up of 9 years, the breast saves the lives of breast cancer patients,” Inter- there was no statistically significant difference in local re- national Journal of Surgical Oncology, vol. 2020, Article ID currence-free survival (P � 0.57), mastectomy-free survival 8709231, 8 pages, 2020. (P � 0.38), distant DFS (P � 0.98), and OS (P � 0.3) [23]. [6] B. Fisher, J. Bryant, J. J. Dignam et al., “Tamoxifen, radiation In another study conducted in our center, we compared therapy, or both for prevention of ipsilateral breast tumor local recurrence in IOERT as a radical dose with EBRT, and recurrence after lumpectomy in women with invasive breast there was no significant recurrence between groups cancers of one centimeter or less,” Journal of Clinical On- (P � 0.335) [24]. Montpelier delivered 21 Gy IOERT for 42 cology, vol. 20, pp. 4141–4149, 2001. patients between 2004 and 2007. With 6 years of follow-up, [7] S. Darby, P. McGale, C. Correa et al., “Effect of radiotherapy local recurrence was 9.5% [25]. A different approach to after breast-conserving surgery on 10 year recurrence and 15 radiotherapy by doing IORT may thus be indicated. year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomized trials,” Lancet, vol. 378, pp. 1707–1716, 2011. 5. Conclusions [8] K. S. Hughes, L. A. Schnaper, J. R. Bellon et al., “Lumpectomy plus tamoxifen with or without irradiation in women age 70 IORT can be a preferred treatment modality to WBRT years or older with early breast cancer: long-term follow-up of because of its noninferior outcomes, and in some conditions, CALGB 9343,” Journal of Clinical Oncology, vol. 31, no. 19, using better patient selection for delivering a radical dose by pp. 2382–2387, 2013. IORT, it has superior outcomes compared to EBRT. Patient [9] J. A. Reisz, N. Bansal, J. Qian, W. Zhao, and C. M. Furdui, convenience is one advantage of IORT, in which the patient “Effects of ionizing radiation on biological molecules- does not spend a great deal of time in radiotherapy centers mechanisms of damage and emerging methods of detection,” for a long time, and it protects the patient from EBRT Antioxidants & Redox Signaling, vol. 21, no. 2, pp. 260–292, complications. 2014. [10] W. F. Athas, M. Adams-Cameron, W. C. Hunt, A. Amir-Fazli, We could expand our descriptions for patient selection and C. R. Key, “Travel distance to radiation therapy and in the IORT groups and deliver IORT even to younger receipt of radiotherapy following breast-conserving surgery,” patients, larger tumor sizes, and other histologies, such as JNCI: Journal of the National Cancer Institute, vol. 92, no. 3, ILC and DCIS. We could develop IORT usage for in-breast pp. 269–271, 2000. tumor recurrences and use BCS with IORT in these cases. [11] S. F. Shaitelman, P. J. Schlembach, I. 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International Journal of Surgical OncologyHindawi Publishing Corporation

Published: Apr 16, 2021

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