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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 994-998

Intraoperative radiotherapy with electrons as partial breast irradiation in limited stage breast cancer: Early term clinical and cosmetic outcomes


1 Department of Radiation Oncology, Gaziosmanpasa University, Tokat, Turkey
2 Department of Radiation Oncology, Ankara Memorial Hospital, Ankara, Turkey
3 Department of Radiation Oncology, Ankara Oncology Hospital, Ankara, Turkey
4 Department of Surgery, Ankara Oncology Hospital, Ankara, Turkey

Date of Web Publication4-Oct-2019

Correspondence Address:
Gülhan Güler Avci
Department of Radiation Oncology, Gaziosmanpasa University, Tokat
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_191_17

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 > Abstract 


Purpose: We aimed to report the experience of intraoperative electron radiation therapy (IOERT) with Mobetron (Intraop Medical Incorporated, Santa Clara, CA, USA) as a partial breast irradiation (PBI) for patients with early-stage breast cancer and explanation of IOERT application and present early clinical and cosmetic result.
Materials and Methods: Between November 2012 and February 2014, in Ankara Oncology Hospital, Radiation Oncology Clinic, was performed IOERT as a PBI with a single dose of 21 Gy for 21selected patients. Median tumor size was 1.5 cm (range, 0.6–2.8 cm). Median treatment duration was 2.04 min (range, 1.26–2.44 min). According to final pathology, two patients were found to have close margin and mastectomy was applied. Three cases (two were N1 mic and one case had perineural invasion and tumor size was >2 cm) received whole breast irradiation.
Results: Median follow-up time was 3 years (range, 26–42 months). One patient died because of nonbreast cancer reason, all of the other patients (except one) alive without disease. There was no Grade 3 or 4 toxicities related to the IOERT. Good or excellent cosmesis was revealed 79% (15/19) and 95% (18/19), by physician and patient, respectively.
Conclusion: IOERT, for patients with early-stage breast cancer as a part of breast-conserving treatment, offer patients better cosmetic results with less skin toxicity and increases comfort of patients by shortening duration of treatment time.

Keywords: Cosmesis, intraoperative radiotherapy, partial breast irradiation, toxicity


How to cite this article:
Avci GG, Güney Y, Küçükpilakci B, Çalikoğlu T, Gülçelik MA, Özaslan C. Intraoperative radiotherapy with electrons as partial breast irradiation in limited stage breast cancer: Early term clinical and cosmetic outcomes. J Can Res Ther 2019;15:994-8

How to cite this URL:
Avci GG, Güney Y, Küçükpilakci B, Çalikoğlu T, Gülçelik MA, Özaslan C. Intraoperative radiotherapy with electrons as partial breast irradiation in limited stage breast cancer: Early term clinical and cosmetic outcomes. J Can Res Ther [serial online] 2019 [cited 2019 Nov 13];15:994-8. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/994/244441




 > Introduction Top


Over the last three decades, breast-conserving surgery (BCS) followed by whole breast irradiation (WBI) with additional irradiation to the tumor bed became the standard of approach for the treatment of early-stage breast carcinoma.[1],[2] Partial breast irradiation (PBI) with suitable patient selection and quality assurance (QA) yields similar results to those accomplished with standard WBI.[1],[2] The rationale for PBI is as uniformly reported that the majority of local recurrences occur in nearness to the tumor bed; <20% of LRs appear “elsewhere” in the breast.[3],[4] The fascination of PBI techniques base on reducing the volume treated, with potential decline of normal tissue toxicity and in shortening the treatment time, with a favorable impact on treatment costs and patients' conformity.[5]

Two serious technical advantages of intraoperative electron radiotherapy (IOERT) in comparison to the use of external beam radiotherapy (EBRT) are direct visualization of the target volume with the least risk of missing the tumor bed and the possibility of protecting healthy tissues by moving them away from the way of the radiation beam. Furthermore, it is possible to execute a high dose accurately targeted to a restricted volume while sparing the surrounding of skin, potentially leading to better cosmetic results.[6],[7] In addition, there is no delay of time between surgery and radiotherapy.[7] Frozen section is absolutely one of the limiting aspects of any intraoperative procedure, as the definitive pathology report may contrast the biopsy.[7]

Furthermore, immediate irradiation in the course of surgery has effects on the tumor microenvironment abrogating the proliferative cascade promoted by surgical wound healing. In vitro, wound fluid has been defined to induce tumor cell proliferation and invasion, which can be interrupted by high-dose intraoperative radiotherapy (IORT).[8] Another apparent aspect is the preservation of possible residual tumor cell repopulation between surgery and radiotherapy. In addition, a good oxygenation status of the tumor bed during operation could also be a factor for augmented biological efficacy.[9]

At our institution, the mobile Mobetron (Intraop Medical Incorporated, Santa Clara, CA, USA) has been used for tumor bed boost or PBI in selected breast cancer patients since November 2012. We analyzed our data from a single institution with novel approach IORT using electrons as a PBI, with early clinic and cosmetic outcome.


 > Materials and Methods Top


Patient selection

From November 2012 to February 2014, 21 early stage breast cancer patients received IOERT after BCS as the sole radiation treatment modality. Patients who have undergone PBI were identified by a multidisciplinary council under the leadership of the GEC-ESTRO and ASTRO recommendations.

Our patient selection criteria for the PBI are as follows: unifocal, unicentric invasive carcinoma (ductal, medullary, and tubular), positive estrogen receptors, tumors' diameter ≤2 cm; Grade G1 and G2, at least 2 mm surgical margin, pN0, nonmetastatic disease, and age >50-year-old. No extensive intraductal or lymph vessel invasion, pure DCIS, and lobular histology had to be identified on primary biopsy.

Local evaluation (mammography and breast ultrasound) evaluated precisely the diameter of the tumor (magnetic resonance imaging was optional). Lobular tumors were excluded due to the risk of multifocality. Neoadjuvant treatments were not allowed before surgery.

Intraoperative radiotherapy procedure

Patients received IOERT with a dedicated mobile linear accelerator (Mobetron Intraop Medical Incorporated, Santa Clara, CA, USA), which has four energy levels: 4, 6, 9, and 12 MeV. Circular applicators are available for field sizes between 3 and 10 cm with bevel angles of 0°, 15°, and 30°. The source to surface distance was 50 cm. The dose rate for this machine in the clinical mode is 10 Gy/min, thus giving a maximum treatment time of around 2 min. This machine uses the soft-docking technique.

In our clinic, processes before application of IOERT are as follows; receiving the patient's consent, physical examination, taking photos (two pictures with frontal and profile views), and measuring the circumference of the breast before IOERT for the evaluation of the cosmetic results.

On the day of treatment, before surgery (quadrantectomy with sentinel node biopsy), and following radiotherapy, quality assurance (QA) was performed for each energy. Immediately after the removal of the breast quadrant, the remaining parenchyma should be separated from the pectoralis fascia to place a bolus disk posterior to the parenchyma to protect the thoracic wall, the heart, and the lung. Then mammary gland is temporally restored by suturing. The treated volume should include the entire surgical scar plus a safety margin of 1–2 cm. The gland thickness was measured for eligible energy selection, and the applicator was chosen according to tumor size. The monitor units needed to deliver the prescribed dose (21 Gy) using an electron beam of appropriate energy are calculated. If surgical marjins are clean and sentinel lymph node is negative in frozen, the patient treated after the proceeding of soft docking.

Evaluation of toxicity and cosmetics

Skin and subcutaneous connective tissue toxicity were evaluated with reference to Common Terminology Criteria for Adverse Events, version 4.03. The cosmetic results were evaluated by the same physician and the patient at each visit according to Modified Harvard-Harris Cosmetic Scale [Table 1].
Table 1: Modified Harvard-Harris Cosmetic Scale

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Follow-up

Every patient was evaluated 3 weeks and 3 months for acute toxicity after IOERT. The patients were viewed every 3 months for the first 2 years, every 6 months for years 2 through 5 for complication and recurrence. Photographs taken (two pictures with frontal and profile views) at each visit.

Statistical methods

The primary end-point was to determine the physician assessment rate of good or excellent cosmesis as measured by the Modified Harvard-Harris Cosmetic Scale. We also monitored toxicity. In our study, we report on patients who required additional therapy (mastectomy or whole breast radiotherapy and on patients who received only IOERT.


 > Results Top


Patient characteristics

From November 2012 to February 2014, 21 patients received IOERT after BCS as a PBI in our institution. As of May 31, 2016, median follow-up time was 3 years (range, 26–42 months). One patient died because of nonbreast cancer reason, all of the other patients (except one) alive without disease. Baseline demographic and clinical characteristics are shown in [Table 2]. After final postsurgery pathology results, two patients had positive resection margins and underwent mastectomy and only received hormonotherapy. WBI after IOERT was performed in two patients because of micrometastases in lymph node. In addition, one patient received WBI after IOERT due to tumor diameter (2 cm over) and perineural invasion at final pathology.
Table 2: Patients and characteristics

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In our study, final pathology of several case reported contradict the biopsy and frozen section. These discordances are shown in [Table 3].
Table 3: Discordance of pretreatment evaluation and final pathology

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Treatment delivery

Intraoperative radiation therapy, single doses of 21 Gy was administered to all patients as PBI. The median lucite disk diameter was 6.5 cm (range 5–9 cm) and thickness of lucite disk was 1 cm for all cases. The median circular cone size was 5.5 cm (range, 4–8 cm). For 6 MeV energy used in 86% of patients, the cutout factor was found to be 1410 for median 5.5 cm circular applicator (cone) diameter. For 9 MeV energy, used in remnant patients, the cut-out factor was calculated as 1.444 for the same applicator diameter. The median duration of treatment was 2.04 min (range, 1.26–2.44 min). While 12 of patients only received adjuvant hormonal therapy, the remaining of patients received adjuvant chemotherapy. Treatment characteristics are shown in [Table 4].
Table 4: Treatment characteristics

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Toxicity and cosmetic outcome

Cosmetic outcome was measured by both physician and patient evaluation according to Modified Harvard-Harris Cosmetic Scale [Table 1]. Two cases were not assessed cosmetically due to the mastectomy. Nineteen of patients' cosmetic scale of final examinations is presented in [Table 5]. Good or excellent cosmesis was revealed 79% (15/19) and 95% (18/19), by physician and patient, respectively.
Table 5: Cosmetic evaluation

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There was no Grade 3 or 4 toxicities related to the IOERT. The acute and late side effects noted in the [Table 6].
Table 6: Acute and late toxicities

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 > Discussion Top


There are two large randomized controlled trials (TARGIT and ELIOT) compared with WBI and IORT.[10],[11] In the TARGIT trial,[10] 5-year risk for local recurrence in the conserved breast was 3·3% for TARGIT versus 1·3% for EBRT (P = 0·042). In the TARGIT-arm, patients were randomized to the prepatholopgy and postpathology stratum. TARGIT concurrently with lumpectomy (prepathology,) had much the same results as EBRT: 2·1% versus 1·1% (P = 0·31). EBRT after TARGIT was necessary in 15% of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). Grade 3 or Grade 4 skin complications were significantly reduced with TARGIT.[10] In recent multicentric TARGIT trial,[12] postpatology-delayed TARGIT arm was found to have lower local control compared to both EBRT and prepathology–simultaneous TARGIT arm. Hence, noninferiority was not established for delayed TARGIT stratum. Overall, breast cancer mortality was much the same between groups; however, there were significantly fewer nonbreast cancer deaths with TARGIT (1.4%, 95% confidence interval [CI] 0.8%–2.5% vs. 3.5%, 95% CI 2.3%–5.2%; P = 0.0086) because of fewer deaths from cardiovascular causes in the TARGIT arm.[12]

The another important trial, ELIOT,[11] is a randomized controlled equivalence trial. Women aged 48–75 years with early breast cancer, a maximum tumor diameter of up to 2.5 cm, and suitable for BCS were randomly receive either whole-breast external radiotherapy or IORT with electrons. The 5-year event rate for ipsilateral breast tumor recurrences (IBTR) was 4·4% in IOERT group and 0·4% in the EBRT group (hazard ratio 9·3 [95% CI 3·3–26·3]). In multivariable analysis, tumor size >2 cm, the presence of four or more positive lymph nodes, a poorly differentiated tumor, and triple-negative subtype increased the risk of IBTR. Skin side effects showed a significant difference in favor of the IORT group (P = 0·0002).

The most important disadvantage of IORT is discordance of pretreatment evaluation and final patology. Also in TARGIT trial, due to this discordance, 15% of patients received EBRT after IORT.[10] Recently, in TARGIT trial,[12] prepathology (concurrently with lumpectomy) TARGIT arm was found more effective for local control. The reason of this may be the tissue oxygenation has not yet been intact and the death of the microscopic residual tumor cells with IORT. EBRT is added according to the risk-adaptive strategy in TARGIT trials.[10],[11],[12] We also added EBRT in three patients (14.2%) because of micrometastases in lymph node, tumor diameter (2 cm over), and perineural invasion at final pathology.

The Geneva University Hospital's experience,[13] a total of 52 women were treated with 20 Gy of IORT with the Intrabeam ® system but only 34 patients (65%) were treated with IORT alone since 18 patients (35%) received IORT followed by additional EBRT. Authors purposed to assess early breast and skin toxicity, and they reported Grade 2 lung toxicity in 6 of 52 patients (11.5%). Grade 3 early breast and skin toxicities, consisting of seroma, were found in 13 of 52 patients (25.0%), while 3.8% of patients experienced Grade 4 toxicity after IORT alone. Their results recommend that IORT followed by EBRT may enhance Grade 1 and 2 breast and skin toxicity while Grade 3 and 4 are decreased when IORT is followed by EBRT.[13]

Welzel et al.[14] from Germany evaluated radiation-related quality of life parameters in the first 123 women from a single center participating in the TARGIT-A trial using the quality of life questionnaire C30 (QLQ-C30, version 3), and the Breast Cancer Module (QLQ-BR23) of the European Organisation for Research and Treatment of Cancer. They showed that patients given IORT alone reported less pain, breast, and arm symptoms compared to those who were given EBRT.[14]

The above-mentioned trials demonstrated that IORT is not an inferior treatment. Furthermore, very few skin side effects occurred in the IORT.[10],[11],[12],[13] The most commonly reported side effects associated with IORT are seroma, wound-related complications, fat necrosis, and fibrosis, while skin toxicity is less when compared to EBRT.[6],[10],[11],[12],[13] In this trial, we observed sermoa (n:4), mastitis (n:2), fat necrosis (n:3), fibrosis (n:3), and no toxicity of skin was seen in any of the patients who received only IORT.

Because of less skin toxicity with IORT, excellent or good cosmetic results have been reported over the 80% of cases in several trials.[6],[15] Kimple et al.[6] assessed 56 patients with respect to cosmetic outcome of intraoperative radiation delivered with Mobetron. Cosmetic outcome was measured by both physician and patient evaluation. The median follow-up time was 3.1 years. The results of “good or excellent” were reported 80% and 76%, according to physician and patient, respectively.

In addition, we have same results, in our study, “good or excellent” cosmesis was revealed 79% (15/19) and 95% (18/19), by physician and patient, respectively.

Although, as mentioned above,[6],[10],[11],[12],[13] seroma, wound-related complications, fat necrosis are most common with application of IORT, these side effects can only be seen after single surgery. How much increases of the risk of adding IORT to surgery. Another subject may change the side effect profile on experienced hands during operation (e.g., the diameter of the applicator or acrylic disc used). Rakhra et al.[16] found that the utilization of larger applicators at the time of IORT was associated with an increase in wound complications and fat necrosis. Of all the evaluated risk factors, only applicator size (P < 0.01) had a statistically significant association with an enhancement in complications.

In our trial, we aimed to report our experience of IORT and clinical results. The study was retrospective and nonrandomized. The study lacked a control group and was small. Furthermore, the follow-up was short with a median follow-up.


 > Conclusion Top


IOERT, for well-chosen patients with early-stage breast cancer as a part of breast-conserving treatment, offer patients better cosmetic results with less skin toxicity and increases comfort of patients by shortening the duration of treatment time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Bartelink H, Horiot JC, Poortmans PM, Struikmans H, Van den Bogaert W, Fourquet A, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007;25:3259-65.  Back to cited text no. 1
    
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Krishnan L, Jewell WR, Tawfik OW, Krishnan EC. Breast conservation therapy with tumor bed irradiation alone in a selected group of patients with stage I breast cancer. Breast J 2001;7:91-6.  Back to cited text no. 2
    
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Clarke DH, Lê MG, Sarrazin D, Lacombe MJ, Fontaine F, Travagli JP, et al. Analysis of local regional relapses in patients with early breast cancers treated by excision and radiotherapy. Experience of the Institute Gustave Roussy. Int J Radiat Oncol Biol Phys 1985;11:137-45.  Back to cited text no. 3
    
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van Limbergen E, van den Bogaert W, van der Schueren E, Rijnders A. Tumor excision and radiotherapy as primary treatment of breast cancer. Analysis of patient and treatment parameters and local control. Radiother Oncol 1987;8:1-9.  Back to cited text no. 4
    
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Hepel JT, Wazer DE. A comparison of brachytherapy techniques for partial breast irradiation. Brachytherapy 2012;11:163-75.  Back to cited text no. 5
    
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Kimple RJ, Klauber-DeMore N, Kuzmiak CM, Pavic D, Lian J, Livasy CA, et al. Cosmetic outcomes for accelerated partial breast irradiation before surgical excision of early-stage breast cancer using single-dose intraoperative radiotherapy. Int J Radiat Oncol Biol Phys 2011;79:400-7.  Back to cited text no. 6
    
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Orecchia R, Veronesi U. Intraoperative electrons. Semin Radiat Oncol 2005;15:76-83.  Back to cited text no. 7
    
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Belletti B, Vaidya JS, D'Andrea S, Entschladen F, Roncadin M, Lovat F, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res 2008;14:1325-32.  Back to cited text no. 8
    
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Vaidya JS, Baldassarre G, Massarut S. Beneficial effects of intraoperative radiotherapy on tumor microenvironment could improve outcomes. Int J Radiat Oncol Biol Phys 2009;74:976.  Back to cited text no. 9
    
10.
Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Keshtgar M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014;383:603-13.  Back to cited text no. 10
    
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Veronesi U, Orecchia R, Maisonneuve P, Viale G, Rotmensz N, Sangalli C, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet Oncol 2013;14:1269-77.  Back to cited text no. 11
    
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Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Saunders C, et al. An international randomised controlled trial to compare TARGeted intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial). Health Technol Assess 2016;20:1-88.  Back to cited text no. 12
    
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Vinh-Hung V, Nepote V, Rozenholc A, Vees H, Monnier S, Castiglione-Gertsch M, et al. First year experience with IORT for breast cancer at the Geneva University Hospitals. Transl Cancer Res 2014;3:65-73.  Back to cited text no. 13
    
14.
Welzel G, Boch A, Sperk E, Hofmann F, Kraus-Tiefenbacher U, Gerhardt A, et al. Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: Results from the randomized phase III trial TARGIT-A. Radiat Oncol 2013;8:9.  Back to cited text no. 14
    
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Ruano-Ravina A, Cantero-Muñoz P, Eraso Urién A. Efficacy and safety of intraoperative radiotherapy in breast cancer: A systematic review. Cancer Lett 2011;313:15-25.  Back to cited text no. 15
    
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Rakhra S, Bethke K, Strauss J, Hayes JP, Hansen N, Khan SA, et al. Risk factors leading to complications in early-stage breast cancer following breast-conserving surgery and intraoperative radiotherapy. Ann Surg Oncol 2017;24:1258-61.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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