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Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): An international, prospective, randomised, non-inferiority phase 3 trial
Abstract
After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy.
Having safely piloted the new technique of single-dose targeted intraoperative radiotherapy with Intrabeam, we launched the TARGIT-A trial on March 24, 2000. In this prospective, randomised, non-inferiority trial, women aged 45 years or older with invasive ductal breast carcinoma undergoing breast-conserving surgery were enrolled from 28 centres in nine countries. Patients were randomly assigned in a 1:1 ratio to receive targeted intraoperative radiotherapy or whole breast external beam radiotherapy, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy. Neither patients nor investigators or their teams were masked to treatment assignment. Postoperative discovery of predefined factors (eg, lobular carcinoma) could trigger addition of external beam radiotherapy to targeted intraoperative radiotherapy (in an expected 15% of patients). The primary outcome was local recurrence in the conserved breast. The predefined non-inferiority margin was an absolute difference of 2.5% in the primary endpoint. All randomised patients were included in the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00983684.
1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy. Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy. 1025 (92%) patients in the external beam radiotherapy group received the allocated treatment. At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53-2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39-2.31) in the external beam radiotherapy group (difference between groups 0.25%, -1.04 to 1.54; p=0.41). The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3.3%] of 1113 vs external beam radiotherapy, 44 [3.9%] of 1119; p=0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p=0.002).
For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks.
University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF).
... The application of this technique has been strongly supported by studies like TARGIT-A, an international, prospective, randomized, noninferiority Phase 3 trial that involved the treatment of 1113 patients with IORT and 1119 with EBRT. This report shows a slight difference in recurrence rates between the patients who received IORT and those who received EBRT (1.2% vs. 0.95%) during 4 years of follow-up [12]. However, IORT can lead to a lower risk of long-term side effects, such as damage to the heart, lungs, or skin. ...
... However, with TARGIT-IORT, deaths not related to BC were significantly lower than those with EBRT [10]. Therefore, IORT using low-energy x-rays (20 Gy) has been proven to be a safe and effective technique for EBC treatment [10,12,21]. ...
... Regarding the side effects of IORT, no risk variables were significantly associated with these events in this study. However, a correlation was suspected between the occurrence of side effects and the applicator size used in lumpectomy, which is related to the radiation dose [12,29,33]. In other reports, the presence of fat necrosis or seroma has been higher (11%) than that obtained in this study (0.84%) [14]. ...
Purpose: This study is aimed at investigating the 10-year outcomes of intraoperative radiotherapy (IORT) in Mexican women with early breast cancer (EBC) treated at the Centro Medico ABC, Mexico City.
Methods: A cohort study included women with early-stage invasive ductal carcinoma aged ≥ 45 years without prior oncologic treatment, tumor size≤3.5 cm, cN0M0, positive hormone receptors, margins≥2 mm, negative sentinel lymph nodes, and no extensive lymphovascular invasion. IORT was administered at 20 Gy for 20–30 min after a lumpectomy. Follow-up extended over 10 years and included clinical examinations every 6 months for the first 18 months, followed by annual mammograms and conventional examinations. Patients out of the criteria were excluded from this study because they were referred for additional surgery and/or whole-breast radiation therapy.
Results: The study involved 238 patients with an average age of 61.1 years. The mean tumor size was 12 mm, and the percentages of lymphatic invasion, positive hormone receptors, and HER2/neu overexpression were 12.6%, 90.8%, and 2.1%, respectively. The median follow-up was 66.6 months (range: 1–126 months), and the overall survival and mastectomy-free rate reached 95.7% and 90%, respectively. Thirteen patients showed side effects; four recurrences were recorded, of which 50% were out-field relapses. The 5-year Kaplan–Meier probability of local relapses, mastectomy-free, and overall survival reached 97.5%, 100%, and 98%, respectively.
Conclusions: This is the first 10-year report about the effect of IORT on Mexican women with EBC in the early stages. Strict adherence to the selection criteria in this study resulted in low rates of side effects, mortality, and local recurrences, demonstrating that IORT is an effective treatment alternative for patients with EBC. Studies with a longer follow-up period should be performed, as recurrences can occur in the long term.
... IORT can also be used in combination with external beam radiation therapy (EBRT). For example, IORT may be given as a boost treatment at the time of tumor resection for many body sites including head and neck, 4-6 brain, 7 breast, 8 abdomen, 9 spine, 10 pelvis, 11,12 and sarcomas. 13,14 Multiple trials have demonstrated safety and efficacy of IORT in controlling microscopic disease in the immediate vicinity of the treatment applicator. ...
... The TARGIT-A trial results were first published in 2010 with updates in 2013 and most recently in August 2020. 8,15,16 Radio-biologically, there are several distinct advantages of IORT. For example, IORT with low-kV photon energy has a 1.5-fold relative biological effect (RBE) compared to megavoltage electron beam due to its higher linear energy transfer (LET). ...
... The IORT process reviewed in this report is based on the INTRABEAM PRS 600 (photon radiosurgery system PRS, INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany) which includes a low-energy x-ray source (XRS) emitting 50 kV photons at a high dose-rate ( Figure 1). 8,[22][23][24][25][26][27][28][29] An overview of IORT systems including their clinical applications and safety considerations was provided by the ASTRO emerging technology committee report on electronic brachytherapy. 30 A description of the INTRABEAM system is also available from the product documentation provided by Zeiss. ...
This report covers clinical implementation of a low kV intraoperative radiation therapy (IORT) program with the INTRABEAM® System (Carl Zeiss Meditec AG, Jena, Germany). Based on collective user experience from eight institutions, we discuss best methods of INTRABEAM quality assurance (QA) tests, commissioning measurements, clinical workflow, treatment planning, and potential avenues for research. The guide provides pertinent background information and clinical justification for IORT. It describes the INTRABEAM system and commissioning measurements along with a TG100 risk management analysis to ensure safety and accuracy of the IORT program. Following safety checks, dosimetry measurements are performed for verification of field flatness and symmetry, x‐ray output, and depth dose. Also discussed are dose linearity checks, beam isotropy, ion chamber measurements, calibration protocols, and in‐vivo dosimetry with optically stimulated luminescence dosimeters OSLDs, and radiochromic film. Emphasis is placed on the importance of routine QA procedures (daily, monthly, and annual) performed at regular intervals for a successful IORT program. For safe and accurate dose delivery, tests of important components of IORT clinical workflow are emphasized, such as, dose prescription, pre‐treatment QA, treatment setup, safety checks, radiation surveys, and independent checks of delivered dose. Challenges associated with in‐vivo dose measurements are discussed, along with special treatment procedures and shielding requirements. The importance of treatment planning in IORT is reviewed with reference to a Monte Carlo‐based commercial treatment planning system highlighting its main features and limitations. The report concludes with suggested topics for research including CT‐based image‐guided treatment planning and improved prescription dose accuracy. We hope that this multi‐institutional report will serve as a guidance document on the clinical implementation and use of INTRABEAM IORT.
... In comparison with mastectomy, BCT has shown similar outcomes with superior cosmesis and reduced psychological and emotional trauma, based on multiple randomized trials. [1][2][3][4] Over several decades, multiple sophisticated approaches [5][6][7][8][9] have been developed to deliver radiation to only a portion of the breast. These include intracavitary brachytherapy, various intraoperative (IORT) approaches using either electron beam or low-energy x-rays, as well as external-beam RT using 3dimensional (3D) conformal RT or intensity modulated RT (IMRT). ...
... IORT approaches have the advantage of being 1-day treatments, with the major downside of not knowing the histologic margins before treatment, which can lead to as many as 20% of patients requiring wholebreast radiation and raises concerns about increased local failures resulting from inadequately covering the highestrisk target. 8,9 The major advantage of external-beam radiation is its noninvasive nature and ease of delivery. The disadvantage of this approach is the need to treat a significantly larger volume of tissue, which appears to increase the rate of poor cosmesis. ...
... Based on the results from the study described here, we were able to demonstrate the feasibility and safety of delivering a tumor bed boost dose using the GammaPod stereotactic system for patients undergoing BCT. This study produced results similar to those reported for targeted IORT (TARGIT trial), 8,9,27 which used low-energy photons intraoperatively to deliver radiation to the tumor bed in a single-fraction approach immediately after surgical excision of the tumor. Initial reports of TARGIT followed by whole-breast radiation demonstrated 5-year local recurrence rates <2% with no grade 3 side effects. ...
Purpose
Radiation therapy for early-stage breast cancer is typically delivered in a hypofractionated regimen to the whole breast followed by a tumor bed boost. This results in a treatment course of approximately 4 weeks. In this study, the tumor bed boost was delivered in a single fraction as part of a safety and feasibility study for FDA clearance of the device.
Methods and Materials
Eligible women with early-stage breast cancer underwent lumpectomy followed by radiation therapy. Patients underwent breast immobilization using a system specific to the GammaPod followed by CT simulation, boost treatment planning, and boost treatment delivery all in a single treatment day. Patients then started whole-breast radiation therapy within 1 week of the boost treatment. Patients and treatments were assessed for safety and feasibility. Acute toxicities were recorded.
Results
A single-fraction boost of 8 Gy was delivered to the tumor bed before a course of whole-breast radiation. The GammaPod treatment was successfully delivered to 14 of 17 enrolled patients. Acute toxicities from all radiation therapy, inclusive of the boost and whole-breast radiation, were limited to grade 1 events.
Conclusions
The GammaPod device successfully delivered a single-fraction boost treatment to the tumor bed with no change in expected acute toxicities. The results of this study led to FDA clearance of the device through the Investigational Device Exemption process at the FDA. The GammaPod is in clinical use at 4e institutions nationally and internationally, with additional sites pending in 2023.
... Увеличение числа больных с локализованными формами РМЖ в развитых странах привело к росту органосохраняющих операций, что позволило обеспечить улучшение качества жизни этого контингента [3]. ...
... Согласно 4-шкальной оценке косметических результатов, следует отметить, что на сроке 6 мес «прекрасный» и «хороший косметический эффект» был выше в группе Б и он составил 81,4% против 62,5% в группе А (табл. 3,4). Это было связано с наличием дефектов в области введения интрадьюсеров и дополнительной пигментации в данной области. ...
Relevance. Breast cancer is the first most common cancer in women not only in Russia, but also around the world. In Russia in 2021, there were 76 000 women diagnosed with breast cancer. As a result of screening programmes, preventive examinations, and educational work, the detection rate of the disease at stages I–II has reached 72%. This determines the implementation of organ-preserving surgical interventions, but a postoperative course of radiotherapy can significantly worsen the cosmetic result. Materials and methods. In our work, we analyzed the cosmetic results in 166 patients who received surgical treatment including lumpectomy for breast cancer with cT1сN0M0 stage. All patients had a luminal, HER2 negative tumor subtype. In accordance with the treatment methods, the main clinical group A (n=80) was formed, which included women who underwent organ-preserving surgical treatment and multifractional high-dose rate brachytherapy with a dose of 1.7 Gy ×2 times a day up to a dose of 34 Gy. Group B (n=86) included patients who underwent organ-preserving surgery and standard radiation therapy with a dose of 2 Gy per day up to a dose of 50 Gy. The groups were comparable in molecular biological characteristics, age and number of patients. Results. According to the 4-scale assessment of cosmetic results, it should be noted that after 6 months, “excellent” and “good cosmetic result” was higher in group B and it was 81.4% compared to 62.5% in Group A. This was due to the defects in the area of introducers placement and additional pigmentation in this area. According to our data, at 24 months there was an increase in “satisfactory” results in the group with external beam radiation therapy, which was associated with the occurrence of late radiation injuries, and the group with interstitial radiation therapy has better cosmetic results of 87.5% compared to 77.9%, as well as fewer satisfactory results: 12.5% compared to 22.1%.To receive a subjective assessment from the patients, we used a questionnaire with a 10-point scale. When studying questionnaires, it was noted that in group A, women were more satisfied with the cosmetic results, which was associated not only with a less scope of surgical intevention (lumpectomy versus sectoral resection), which affected the shape of the mammary gland, but also in this group there was less swelling and thickening of the breast skin and changes in the breast tissue itself. Conclusions. Brachytherapy in patients with early stages of breast cancer has good cosmetic results, which has a positive effect on the emotional state of women.
... Nodal metastases was a notable risk factor for LRR (39). Despite the institute's protocol mandating a negative SLNB for IORT eligibility, 15.2% of patients exhibited a single nodal metastasis upon the final pathology, surpassing the rates reported in other studies (31,(40)(41)(42)(43)(44)(45). Although the TARGIT-A and ELIOT trials indicated that lymph node involvement of less than three does not necessary contraindicate IORT, patients with positive nodes typically require more aggressive treatment (40,41,46). ...
... Despite the institute's protocol mandating a negative SLNB for IORT eligibility, 15.2% of patients exhibited a single nodal metastasis upon the final pathology, surpassing the rates reported in other studies (31,(40)(41)(42)(43)(44)(45). Although the TARGIT-A and ELIOT trials indicated that lymph node involvement of less than three does not necessary contraindicate IORT, patients with positive nodes typically require more aggressive treatment (40,41,46). Consistent with this, among the 17 patients with positive nodal involvement in the analysis, all underwent salvage surgery and chemotherapy, with two also received irradiation, resulting in only one case of local recurrence. ...
Background
Intraoperative radiation therapy (IORT) and whole breast irradiation (WBI) are both effective adjuvant radiotherapy methods for ductal carcinoma in situ (DCIS) or early-stage breast cancer (BC) patients undergoing breast-conserving surgery (BCS). We aim to evaluate the long-term oncological efficacy and refine patient selection criteria based on our findings.
Methods
Female patients who underwent either IORT or WBI from January 2016 to December 2019, with a minimum follow-up of 12 months were collected. IORT was administered as a single fraction of 20 Gray (Gy) to the lumpectomy cavity using the Axxent electronic brachytherapy system, while WBI consisted of a standard fractionation of 50 Gy in 25 fractions, along with a reduced boost of 10 Gy. The clinicopathologic characteristics and oncological outcomes were retrospectively analyzed.
Results
A total of 247 patients were enrolled, comprising 164 with BC and 83 with DCIS. Among them, 112 underwent IORT, and 135 received WBI after BCS. The median age was 62.2 years, with median tumor sizes of 1.5 cm for BC and 1.2 cm for DCIS. At a median follow-up of 64.6 months, IORT demonstrated 11 locoregional recurrences (LRR), 1 metastasis, and 1 death, compared to 4 LRR, 5 metastases, and 2 deaths in the WBI group. WBI yielded significantly higher locoregional control (97.0% vs. 90.2%, p = 0.033), although metastasis-free (96.3% vs. 99.1%, p = 0.166) and overall survival rates (98.4% vs. 99%, p = 0.688) did not differ. The LRR rate was significantly higher in the IORT group among the DCIS or BC patients (p = 0.043). The hazard ratio for locoregional recurrence significantly increased in estrogen-receptor-negative (ER-) patients in both univariate analysis (HR = 4.98, 95% CI = 1.76-14.09, p = 0.002) and multivariate analysis (HR = 40.88, 95% CI = 1.29-1297.84, p = 0.035). Additionally, IORT was associated with increased LRR in the multivariate analysis (HR = 4.71, 95% CI = 1.16-19.06, p = 0.030).
Conclusion
At a long-term follow-up, the LRR rate was higher in the BCS followed by IORT, without significant differences in metastasis-free or overall survival rates. Our data confirmed the importance of exclusion ER- patients for IORT.
... Увеличение числа больных с локализованными формами РМЖ в развитых странах привело к росту органосохраняющих операций, что позволило обеспечить улучшение качества жизни этого контингента [4]. ...
... Также при обобщении результатов 7 исследований сроком наблюдения от 15 до 54 мес (в среднем 34 мес), суммарно включающих 485 женщин, получивших суммарную очаговую дозу (СОД) 38,5 Гр за 10 фракций, до-стигнут хороший косметический эффект у 81%, а количество местных рецидивов отмечено от 6% до 0, в среднем 1% [4,12,13]. ...
Thanks to the introduction of new screening programs, the emergence rate of novel anticancer drugs and the detection rate of early-stage breast cancer in Russia increase year by year. Organ preservation treatment, after which radiation therapy has to be performed, is the most common type of surgical treatment used in this cohort of patients. Today, various treatment methods are used, the most common is external beam radiation therapy, however, brachytherapy of breast cancer is also used.
... Another therapeutic approach is accelerated partial breast irradiation (APBI), in which only a part of the breast is irradiated in a shorter timeframe compared to standard EBRT. Techniques used for APBI include balloon brachytherapy, multicatheter technique, external beam accelerated partial-breast irradiation and intraoperative radiotherapy with low energy x-rays (IORT), providing comparable local control as well as an excellent cosmetic outcome compared to EBRT [5][6][7][8][9][10][11]. For electron intraoperative radiotherapy (ELIOT), long-term results of the ELIOT trial confirm higher rates of ipsilateral breast tumor recurrence (IBTR) in the ELIOT group than in the group receiving whole breast irradiation, without any differences in overall survival [12]. ...
... According to the TARGIT-A trial, no differences were shown in the two groups regarding the secondary endpoint wound infections, whereas grade 3 and 4 toxicities were significantly lower in the experimental arm. In a selected patient population with early breast cancer, IORT as the only radiotherapeutic procedure may shorten or completely replace the external irradiation that usually follows surgery and is therefore convenient for the patients [10]. This might also be helpful to shorten treatment time during a pandemic [18]. ...
Purpose
The aim of this study is to identify pre- and intraoperative factors indicating the feasibility of intraoperative radiotherapy (IORT) during breast-conserving surgery (BCS).
Materials and methods
From January 2018 to December 2019, a total of 128 women undergoing BCS due to early breast cancer were included in this prospective observational study, independent of whether IORT was planned or not. Patient and tumor characteristics as well as surgical parameters that could potentially influence the feasibility of IORT were recorded for the entire collective. In addition, a preoperative senological assessment was performed and analyzed to assess the feasibility of IORT. Logistic regression was then used to identify relevant preoperative parameters and to generate a formula predicting the feasibility of IORT.
Results
Of the 128 included women undergoing BCS, 46 were preoperatively rated to be feasible, 20 to be questionably feasible for IORT. Ultimately, IORT was realized in 30 patients. The most frequent reasons for omission of IORT were insufficient tumor-to-skin distance and/or an excessively large tumor cavity. Small clinical tumor size and large tumor-to-skin distance according to preoperative ultrasound were significantly related to accomplishment of IORT.
Conclusion
We observed that preoperative ultrasound-based tumor–skin distance is a significant factor in addition to already known parameters to predict feasibility of IORT. Based on our findings we developed a formula to optimize IORT planning which might serve as an additional tool to improve patient selection for IORT in early breast cancer.
... 13,14 The idea behind IORT in breast-conserving surgery is to deliver a high, single dose in the most precise way to the areas with the highest risk of subclinical, tumour cell contamination through direct visualisation. The dose of IORT is usually [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Gy, which has the advantages of shortening the treatment course, precisely locating the target area, and improving the radiobiological effect on the tumour, thus compensating for the shortcomings of conventional radiotherapy. ...
... 15,16 Similarly, preliminary results from TARGIT-A trial showed that the local control rate of IORT alone after breast-conserving surgery was noninferior to that of postoperative external radiotherapy in patients aged ≥45 years with early-stage breast cancer; however, the 5-year local recurrence rate was significantly higher in the IORT group than in the external, radiotherapy group. 17,18 Therefore, the effectiveness of IORT alone remains controversial. ...
Background
There is no definitive answer regarding the efficacy of intraoperative radiotherapy (IORT) as a tumour bed boost for patients with early-stage breast cancer. The purpose of this meta-analysis was to summarise the available evidence and explore the efficacy and safety of IORT combined with whole breast irradiation (WBI) versus conventional radiotherapy in women with early-stage breast cancer who underwent breast-conserving surgery.
Methods
The PUBMED, MEDLINE, EMBASE, Web of Science, and Cochrane Library databases were searched from inception to December 31, 2022. We collected studies on the efficacy, cosmetic outcome, and safety of IORT boost combined with WBI compared with those of conventional radiotherapy in patients with early-stage breast cancer after breast-conserving surgery. Two authors independently performed the literature selection and data extraction. The quality of the randomised, controlled trials (RCTs) was assessed according to the PEDro scale. The quality of non-RCTs was assessed according to the Methodological Index for Non-Randomised Studies. Risk ratios (RRs) for the local recurrence rate (LRR), distant metastasis rate (DMR), disease-free survival (DFS), cosmetic outcome, and toxicity were pooled using fixed or random effects models. Meta-analysis of the included studies was performed by using RevMan 5.3 software.
Results
Nine studies, including one RCT and eight non-RCTs, with a total of 3219 patients were included. In terms of LRR, there was no significant benefit of IORT boost+WBI over conventional radiotherapy (with or without the tumour bed boost) (RR = 0.77, 95% confidence interval (CI): 0.54–1.09, P = 0.14), but a trend towards benefit could be identified. There was a significant reduction in DMR in the IORT boost+WBI group (RR = 0.63, 95% CI: 0.46–0.85, P = 0.003) and a significant improvement in DFS (RR = 0.40, 95% CI: 0.25–0.65, P = 0.0002). Exploratory subgroup analysis showed that the DMR and DFS of the electron boost group were significantly better than those of conventional radiotherapy group, and there was a tendency for LRR to improve in the electron boost group. However, the LRR, DMR, and DFS did not effectively improve in the x-ray boost group. In terms of appearance and toxicity, there were no significant differences in cosmetic outcome, fibrosis, and hyperpigmentation between the two groups (RR = 0.99, 95% CI: 0.91–1.07, P = 0.78; RR = 1.02, 95% CI: 0.41–2.56, P = 0.96; RR = 0.42, 95% CI: 0.10–1.72, P = 0.23), but the incidence of oedema was significantly reduced in the IORT boost+WBI group (RR = 0.27, 95% CI: 0.13–0.59, P = 0.0009).
Conclusions
IORT boost+WBI is more effective than conventional radiotherapy after breast-conserving surgery in patients with early-stage breast cancer, and electron boost exhibits better efficacy than x-ray boost. In addition, the cosmetic and safety profiles of IORT boost+WBI are not inferior to those of conventional radiotherapy.
... needle, and the needle with the 40 mm spherical applicator, see figure 3. The bare needle was selected because this is the configuration on which the manufacturers measurements and documentation is based, for release to the user. The 40 mm spherical applicator is common in clinic to treat surgical bed after tumor resection, and it is the standard in the TARGIT clinical trial [14]. ...
... The bare needle was selected because this is the configuration on which the manufacturers measurements and documentation is based, for release to the user. The 40 mm spherical applicator is common in clinic to treat surgical bed after tumor resection, and it is the standard in the TARGIT clinical trial [14]. ...
In this work, a methodology to determine the absorbed dose rate to water distribution from electronic brachytherapy (eBT) units is suggested. It involves measuring directly in a full scatter water tank with small active detectors whose energy response at low X-ray photon energies have been previously characterized. Dose distributions of an INTRABEAM PRS 500 system in two configurations — bare needle and with the spherical applicator of 40 mm diameter — were measured in water using the Exradin A26 ionization chamber and the PTW 60019 microDiamond detector. The continuous energy response of these two detectors in terms of air kerma from 5 keV to 70 keV (eBT energy range) was available from a previous calibration at several X-ray radiation qualities. Here, it is converted to the response in absorbed dose to water using correction factors obtained with Monte Carlo (MC) particle transport simulations. The detectors were modelled using the MCNP code. The air kerma calibration factors were simulated and compared with measurements to refine and validate the models. A series of simulations of the experimental arrangement of the INTRABEAM and the detector were carried out for determining the system specific detector correction factors. These values are distance-dependent due to the steep dose gradient and the remarkable spectral changes around the eBT source in water. The dose rate with distance from the source, the radial and the polar distributions of the INTRABEAM are reported and compared with the manufacturers supplied data. This work is an effort to provide traceability for detectors and measurement procedures for the determination of 3D dose distributions as part of the European joint research project “Primary standards and traceable measurement methods for X-ray emitting electronic brachytherapy devices” (18NRM02 PRISM-eBT).
... The efficacy of IORT with Intrabeam ® system was investigated in TARGIT-A Trial, an international phase 3, randomised clinical trial that compared PBI with TARGIT-IORT with standard whole breast radiotherapy in early-stage breast cancer patients. In its first publications (3,4) in-breast tumour recurrence (IBTR) risk of patients treated with TARGIT-IORT immediately after lumpectomy resulted similar to standard EBRT (5-years IBTR=2.1% (IORT) vs. 1.1% (EBRT), p=0.31), whereas delayed (post-pathology) TARGIT-IORT was not non-inferior (5-years IBTR= 5.4 (IORT) vs. 1.7(EBRT), p=0.069). ...
Introduction
Randomised evidence supports the use of partial breast irradiation (PBI) with targeted intraoperative radiotherapy (TARGIT-IORT) for early stage breast cancer, but prospective data from real-world adoption of this technique is also important. The aim of this study was to determine if the outcome reported in TARGIT-A trial could be replicated in large cohort of early stage breast cancer treated with TARGIT-IORT.
Methods
This prospective observational study analysed all patients treated with TARGIT-IORT between 2004 and 2021 in a single national cancer institute. TARGIT-IORT during lumpectomy was performed according to the risk-adapted TARGIT-A protocol using the Intrabeam® device. We analysed the completeness of follow up, 5-year in-breast-tumour-recurrence (IBTR), long term local recurrence free survival, distant disease-free survival, overall survival and breast-cancer-related survival, using the Kaplan-Meier method. A covariate analysis was performed to investigate risk factors for IBTR. We also analysed high grade toxicity events.
Results
The study included 814 patients and the a median follow up was 72 months. The majority of patients (60.3%) received TARGIT-IORT as PBI modality (“exclusive IORT” group); 39.7% received additional EBRT. There was no significant difference between the 5 years IBTR for the whole study population and the “exclusive IORT” cohort (1.6% (95%CI=1.1-2.1%) and 2.5% (95%CI=1.7%-3.3%) respectively). 5 years overall survival and tumour related survival were >95%. In 21% of patients with recurrence, breast was preserved. Radiotherapy toxicity (CTCAE Grade>2) was very rare (0.9%).
Conclusions
This large single institute study found that breast cancer control and survival outcomes with TARGIT-IORT were consistent with TARGIT-A trial results. This “real world” experience confirmed that the randomised evidence showing the value of TARGIT-IORT as partial breast irradiation modality that can be replicated in routine clinical practice.
... The long-term results of the international randomised TARGIT-A trial (n=2298) in which TARGIT-IORT was compared with EBRT found TARGIT-IORT to be effective as whole breast radiotherapy, reduced non-breast cancer deaths and improved overall survival in those with grade 1 and grade 2 cancers. [4][5][6][7][8][9][10][11][12] To date, several studies have investigated patients' experiences with TARGIT-IORT quantitatively. [13][14][15][16][17][18] These studies gathered information about patients' quality of life (QoL) during and after treatment via questionnaires and have concluded that patients receiving TARGIT-IORT report high QoL scores 13 and better emotional well-being, less pain, fewer breast and arm symptoms compared with patients receiving EBRT. ...
Objective
To gather a deep qualitative understanding of the perceived benefits and impacts of External-Beam RadioTherapy (EBRT) and TARGeted Intraoperative radioTherapy (TARGIT-IORT) using Intrabeam to assess how the treatments affected patient/care partner experiences during their cancer treatment and beyond.
Design and participants
A patient-led working group was established to guide study design and to help validate findings. Patients with experience of receiving EBRT or TARGIT-IORT were purposively sampled by Hampshire Hospitals NHS Foundation Trust. These patients had been offered both regimens as per their clinical features and eligibility. Semistructured interviews were conducted with 29 patients and care partners with lived experience of either EBRT (n=12, 5-day FAST-Forward regimen and n=3, 3-week regimen) or TARGIT-IORT (n=14). Thematic analysis was then carried out by two coders generating 11 themes related to EBRT or TARGIT-IORT.
Setting
Semistructured interviews were conducted virtually via Zoom during February and March 2023.
Results
A number of procedural grievances were noted among EBRT patients. EBRT was perceived as being disruptive to normal routines (work, home and travel) and caused discomfort from side effects. TARGIT-IORT was perceived by patients and care partners as the safer option and efficient with minimal if any disruptions to quality of life. The need for timely accessible information to reduce anxieties was noted in both cohorts.
Conclusions
This qualitative study found that patients perceived EBRT as being greatly disruptive to their lives. In contrast, the one-off feature of TARGIT-IORT given while they are asleep during surgery gives them the feeling of stamping out the cancer without conscious awareness. These insights can help healthcare staff and policy-makers further justify the incorporation of the treatment favoured by these patient perceptions (TARGIT-IORT) more widely in routine practice. Further research is planned to explore TARGIT-IORT in more diverse populations and in the 35 countries where it is an established treatment option.
... Grit Welzel et al reported the IORT group had less postoperative pain in the whole body, arm, and breast, and better functional activity (p < 0.01) compared to EBRT. 11 According to TARGIT-A, 40 grade III-IV radiation-related complications such as dermatitis, telangiectasis, and pain at the radiation site were significantly lower in the IORT group than in the EBRT group 20 (median follow-up: 4 years, 0.5% vs. 2.1%, p = 0.002). Chronic toxicities such as skin fibrosis and telangiectasis were also lower in the IORT group than that in the EBRT group (5.9% vs. 18.1%, 0 vs. 17.7%). ...
Objective
This study aimed to verify if intraoperative radiotherapy (IORT) can achieve the same survival outcome as whole‐breast external beam radiotherapy (EBRT) in early breast cancer after breast‐conserving surgery (BCS), and to explore the suitable candidates that can safely receive IORT after BCS.
Methods
Eligible post‐BCS patients who received IORT or EBRT were included in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. Risk factors that affected 5‐year overall survival (OS) or breast cancer specific survival (BCSS) were identified by Cox proportional hazards regression analysis. Clinical characteristics, OS, and BCSS were comparatively analyzed between the two treatment modalities.
Results
The survival analysis after propensity score matching confirmed that patients who received IORT (n = 2200) had a better 5‐year OS than those who received EBRT (n = 2200) (p = 0.015). However, the two groups did not differ significantly in 5‐year BCSS (p = 0.381). This feature persisted even after multivariate analyses that took into account numerous clinical characteristics. Although there was no significant difference in BCSS between different subgroups of patients treated with IORT or EBRT, patients over 55 years of age, with T1, N0, non‐triple negative breast cancers, hormone receptor‐positive, and histologic grade II showed a better OS after receiving IORT.
Conclusion
In low‐risk, early‐stage breast cancer, IORT was not inferior to EBRT considering 5‐year BCSS and OS. Considering the equivalent clinical outcome but less radiotoxicity, IORT might be a reasonable alternative to EBRT in highly selective patients undergoing BCS.
... Additionally, this synthetic process can be used at standard pressure and temperature which saves a significant amount of energy [8][9][10][11][12]. The process involves utilizing different plant components, such as root extract, encompassing seeds, leaf extract, stem extract, and fruit extract, which are employed in this process and act like reducing agents and stabilizers [13][14][15][16][17][18]. Between various metal oxide nanoparticles, gold nanoparticles (Au NPs) were more useful in the field of nanochemistry and nanomedicine due to their efficient anti-microbial, bacterial and cancerous effects as well as their chemical stability [8,9]. ...
This article describes a new type of core–shell pattern Fe3O4 nanoparticle (Au/CS-agar@Fe3O4) that was developed using Au NPs and chitosan-agarose composite. Our goal in catalytic exploration was to synthesize 5-substituted-1H-tetrazoles via click synthesis using aryl halides. By this method, using K4[Fe(CN)6] as a nontoxic CN resource, we treated a variety of aryl halides (Cl, Br, and I) using the highly effective and reusable Au/CS-agar@Fe3O4 catalyst, catalyzing the [3 + 2]-cycloaddition of the corresponding aryl nitriles with NaN3 to the successive one-pot solvent-free preparation at 120 °C of 5-substituted-1H-tetrazoles. The various substrates provided a yield in the range of 70–96% after the reaction of 12 h. The catalyst's robustness was supported by tests for leaching, hot filtration, and catalyst reusability nine times in a row. In the medicinal part, the anticancer properties of Au/CS-agar@Fe3O4 nanocomposite against lung cancer cell lines were determined. In vitro experiments, after 3–4 passages, the cancer cells (NCI-H1563, NCI-H1573, NCI-H1975, and NCI-H661) and normal cell (HUVEC) were prepared in terms of morphology and number. After segregating the cells from the flask surface by trypsin–EDTA, cell viability was assessed and counted, and 3 × 10³ cells were cultured with or without nanoparticles in 96 wells. IC50 of Au/CS-agar@Fe3O4 nanocomposite was 160, 173, 142, and 212 on NCI-H1563, NCI-H1573, NCI-H1975, and NCI-H661 cancer cells. In this study, the highest antioxidant efficacy on DPPH was reported approximately 100% at 1000 μg/ml. The antioxidant IC50 of Au/CS-agar@Fe3O4 nanocomposite was 254 µg/mL.
... Intraoperative radiotherapy with a single high radiation dose administered following tumor resection, intraoperative radiotherapy (IORT), a novel and non-conventional form of radiotherapy, can eradicate any remaining tumor cells [99]. A wide range of cancers, including breast, pancreatic, lung, and colon cancers, have been treated with IORT [100][101][102]. ...
This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas (LGG), the predominant primary tumors in the central nervous system. With a general incidence rate of 5.81 per 100000, gliomas pose a significant global concern, necessitating advancements in treatment techniques to reduce mortality and morbidity. This review places a particular focus on immunotherapies, discussing promising agents such as Zotiraciclib and Lerapolturev. Zotiraciclib, a CDK9 inhibitor, has demonstrated efficacy in glioblastoma treatment in preclinical and clinical studies, showing its potential as a therapeutic breakthrough. Lerapolturev, a viral immunotherapy, induces inflammation in glioblastoma and displays positive outcomes in both adult and pediatric patients. Exploration of immunotherapy extends to Pembrolizumab, Nivolumab, and Entrectinib, revealing the challenges and variabilities in patient responses. Despite promising preclinical data, the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment, emphasizing the critical need to understand resistance mechanisms. The review also covers the success of radiation therapy in pediatric LGG, with evolving techniques, such as proton therapy, showing potential improvements in patient quality of life. Surgical treatment is discussed in the context of achieving a balance between preserving the patient’s quality of life and attaining gross total resection, with the extent of surgical resection significantly influencing the survival outcomes. In addition to advancements in cancer vaccine development, this review highlights the evolving landscape of LGG treatment, emphasizing a shift toward personalized and targeted therapies. Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG.
... Complicating the results further, histopathologic factors that trigger additional treatment varied between studies and even among different treatment centers in the same study. 8,14,20 Recent literature has suggested the possibility of de-escalation using hypofractionation. The UK Fast-Forward 3 , the FlorenceTrial, 23 and the Netherlands trial 24 all have reported 5-years local recurrence rates ranging from 1.4 to 3.7% with 5 or 10 days of treatment. ...
Background:
Randomized trials have shown that risk-adapted intraoperative radiation therapy (IORT) after breast-conserving surgery for low-risk breast cancer patients is a safe alternative to whole-breast radiation therapy (WBRT). The risk-adapted strategy allows additional WBRT for predefined high-risk pathologic characteristics discovered on final histopathology. The greater the percentage of patients receiving WBRT, the lower the recurrence rate. The risk-adapted strategy, although important and necessary, can make IORT appear better than it actually is.
Methods:
Risk-adapted IORT was used to treat 1600 breast cancers. They were analyzed by the intention-to-treat method and per protocol to better understand the contribution of IORT with and without additional whole-breast treatment. Any ipsilateral breast tumor event was considered a local recurrence.
Results:
During a median follow-up period of 63 months, local recurrence differed significantly between the patients who received local treatment and those who received whole-breast treatment. For 1393 patients the treatment was local treatment alone. These patients experienced 79 local recurrences and a 5-year local recurrence probability of 5.95 %. For 207 patients with high-risk final histopathology, additional whole-breast treatment was administered. They experienced two local recurrences and a 5-year local recurrence probability of 0.5 % (p = 0.0009).
Conclusions:
Whole-breast treatment works well at reducing local recurrence, and it is a totally acceptable and necessary addition to IORT as part of a risk-adapted program. However, the more whole-breast treatment that is given, the more it dilutes the original plan of simplifying local treatment and the less we understand exactly what IORT contributes to local control as a stand-alone treatment.
... The direct visualization and positioning of the applicator on the tumor bed led to better local control (LC) and disease-free survival (DFS) after surgical resection, allowing a better intraoperative protection of adjacent healthy structures [13,14]. Beyond the clinical and prognostic advantages, IORT is also beneficial for early-stage BC patients who cannot undergo long and intensive courses of adjuvant external beam (EB)RT due to organizational and/or personal problems, for patients who live at long distances from hospital and for patients with comorbidities not suitable for EBRT [15,16]. In the last two decades, the introduction of dedicated mobile accelerators increased the popularity of intraoperative electron RT (IOERT), and the criteria for patient selection were reviewed in 2020 by the European Society for Radiotherapy and Oncology (ESTRO) [17]. ...
Simple Summary
A retrospective observational study was proposed to evaluate the clinical response rate and cosmetic outcome after full-dose intraoperative electron radiotherapy (IOERT) in early low-risk breast cancer treated with conserving surgery. 162 patients were included in this analysis (median follow-up: 54 months, range: 1–98 months). IOERT was delivered with a dose of 21 Gy at 90% isodose. The overall response rate was 97.5% (CI 95%: 0.93–0.99%). Locoragional relapse occurred in 2.5% of patients. No patient showed distant metastases. No patient showed radiation-related acute complications, 3.7% of patients late G2–3 toxicity. Only 3.7% of patients showed poor cosmetic results. The results highlighted the safety and effectiveness of the full-dose IOERT treatment for highly selected patients.
Abstract
To evaluate the clinical response rate and cosmetic outcome after full-dose intraoperative electron radiotherapy (IOERT) in early breast cancer (BC) treated with conserving surgery. Inclusion criteria were: >60 years old, clinical tumor size ≤2 cm, luminal A carcinoma, patological negative lymph nodes, excluded lobular carcinoma histology. IOERT was delivered with a dose of 21 Gy at 90% isodose. Clinical, cosmetic and/or instrumental follow-up were performed 45 days after IOERT, 6 months after the first check, and every 12 months thereafter. Acute and late toxicities were assessed with the CTCAE v.4.03 and EORTC-RTOG scales, respectively. Cosmetic outcome was evaluated using the Harvard/NSABO/RTOG Breast Cosmesis Grading Scale. Overall, 162 consecutive patients were included in this analysis (median follow-up: 54 months, range: 1–98 months). The overall response rate was 97.5% (CI 95%: 0.93–0.99%). Locoragional relapse occurred in 2.5% of patients. No patient showed distant metastases. No patient showed radiation-related acute complications, with 3.7% showing late G2–3 toxicity. Only 3.7% of patients showed poor cosmetic results. Our data confirmed that IOERT is a feasible and valid therapeutic option in low-risk BC patients treated with lumpectomy. A low local recurrence rate combined with good cosmetic results validates the settings of our operative method in routinely clinical practice.
Partial breast irradiation has evolved to deescalate the radiation treatment volume after a breast-conservative surgery. A number of well-designed trials have established APBI for low-risk early breast cancer as effective as whole breast radiation. Several techniques such as brachytherapy, external beam radiation, and intraoperative radiation have been used with nearly similar results. At present, newer trials are evaluating the feasibility of performing such treatment in one to three fractions which will change the paradigm of management.
Breast cancer is the most common cancer among females across the globe and in India, with an incidence of nearly 40 per 100,000 population. Mastectomy has been extensively described as a surgical treatment option since the previous century. In 1894, Halsted introduced the concept of radical mastectomy which comprises en-bloc removal of the breast, overlying skin, pectoralis major, pectoralis minor and level I, II, and III lymph nodes. Nearly, three-quarters of patients in the series of Halsted’s had axillary lymph node metastases. Instead of such advanced disease, he reported only 6% local recurrence and an impressive 3-year survival rate of 38–42%. In 1948, Patey reported no added benefit of removal of the pectoralis major and described a technique known as modified radical mastectomy (MRM), which was further modified by Auchincloss and Madden by preserving both the pectoralis major and the pectoralis minor muscles. This paradigm shift was intending less mutilating surgery without compromising survival outcomes. As a result, by 1980, nearly 70% of all breast cancer surgeries were MRM.
The treatment of early-stage breast cancer is evolving dynamically, with partial-breast irradiation (PBI) as a de-escalation concept for low-risk situations.
Partial-breast irradiation represents a guideline-based option for adjuvant radiation therapy in patients with low-risk breast cancer, provided proper patient selection and techniques are employed. The best data are available for multicatheter brachytherapy and percutaneous PBI, showing similar rates of local recurrences compared to whole-breast irradiation (WBI) as well as improved acute toxicity and disease-related quality of life.
Partial-breast irradiation is an established alternative to WBI and also offers promising development opportunities.
To assess for the first time the safety and feasibility of combining photon-intraoperative radiotherapy (ph-IORT) with hypofractionated whole breast irradiation (h-WBI) in patients referred to primary systemic therapy (PST).
From March 2019 to December 2020, patients referred for breast conservative surgery (BCS) after PST in our institution were prospectively included in the present trial. PST was prescribed to all patients according the ESMO–SEOM guidelines. Once the PST was completed, BCS was discussed in the multidisciplinary tumor board (MTB). 20 Gy were prescribed to the surface of the applicator of an Intrabeam®photon-IORT during BCS. h-WBI (40.5 Gy/2.67 Gy/15frx) was planned to be administered 3-5w after BCS. All patients were treated with hWBI VMAT-Rapid-Arc&Daily Exac-Trac-IGRT. The primary end points of the study were feasibility and safety (grade 3 toxicity rate CTCAE.5.0-scale) of the proposed treatment protocol. The secondary end points included cosmetic results (Harvard Scale), local relapse rate and overall survival.
Thirty-five patients were included in the trial. The median age was 54 years. Tumor size was > 2 cm in all cases. Eighteen patients were N + (51.4%). There was no disease progression during PST. All patients received the planned 20 Gy-ph-IORT boost at the time of BCS and the proposed h-WBI. 31/35 (88,6%) patients started h-WBI within the predefined time period (3–5w after BCS). No patient showed ≥ G3 acute toxicity 3 months after the end of h-WBI. No ≥ G3 late toxicity was observed at 12 months of follow-up and thereafter. Cosmetic results were scored excellent/good in 26 patients (74.2%). After a median follow-up of 52 months, a TNBC patient locally relapsed at 13 months of follow-up.
We demonstrated for the first time that ph-IORT + hWBI is feasible and safe in patients referred to BCS after PST.
Background
Intraoperative radiotherapy (IORT) offers more convenience compared to external beam radiotherapy (EBRT) following breast‐conserving surgery for early‐stage breast cancer. This study describes the implementation of IORT at a metropolitan academic cancer center.
Methods
Demographics, tumor characteristics, margin status, adjunct EBRT, and cosmetic results were retrospectively analyzed in patients undergoing BCS with IORT. IORT consists of 20 gray delivered to the partial mastectomy cavity.
Results
From 2015 to 2020, 171 patients (65.5% African American) were included. Histologically, 104 (60.8%) patients had invasive ductal carcinoma (IDC), while 67 (39%) patients had DCIS only. Seventeen (15.9%) patients with IDC and 12 (8.6%) patients with DCIS had positive margins. There were 15 ipsilateral breast recurrences (8.8%) and three patients (20%) developed systemic disease. Twenty‐five patients (14.6%) underwent adjuvant EBRT. The local recurrence‐free survival at 60 months from date of IORT was 89.4% (95% CI 82.7%–93.6%). For overall survival (OS), 168 (98.2%) patients were alive at a median follow‐up of 51.4 months, and three total deaths were recorded.
Conclusions
IORT is a highly desirable and convenient alternative to EBRT for early‐stage breast cancer especially for patients with poor compliance. IORT has an acceptable ipsilateral recurrence while not precluding adjunct EBRT based upon the final pathologic report.
Background: Intraoperative radiation therapy (IORT) has gained popularity in recent years as an alternative to external beam whole breast radiation therapy (WBRT) for early-stage breast cancer. Here, we report 43-month recurrence and survival outcomes in a multiethnic cohort treated with IORT in a clinical context.
Method: Two hundred and eleven patients with low-risk features were treated with IORT for early-stage breast cancer from 2014 to 2021. Selection criteria were based on Group Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) guidelines: preferably unifocal intraductal carcinoma (IDC), aged>50, tumor size≤2.0 cm, and without lymph node involvement. All patients received 20 Gy of radiation dose during the lumpectomy. Information on patient and tumor characteristics was collected.
Results: The mean age of this cohort was 67.5 years; 95.2% of patients are Jewish, and the rest are Bedouins (4.7%). Most tumors were intraductal carcinoma (97.2%) and stage 1 (94.8%). The mean follow-up time was 43.4 months. Bedouins had larger tumor sizes (mean 1.21 vs. 1.13 cm) and were younger at diagnosis than Jewish patients (mean 65.4 vs. 67.6 years), although the differences are not significant. The overall recurrence rate was 1.4%. One case of local recurrence (0.5%) and two cases of metastasis (0.9%) were observed during the study period. One patient died from metastasis.
Conclusion: Our findings suggest that IORT in selected low-risk patients can achieve an excellent prognosis with low rates of recurrence and metastasis.
Intraoperative radiotherapy (IORT) by low-energy X-rays is a single-fraction modality for tumor bed irradiation following surgery. Two specific machines, including INTRABEAM and Axxent, are available for this purpose. Current study aims to compare the RBE values relevant to produced X-rays by these machines using a hybrid Monte Carlo (MC) simulation approach. Validated MC models of INTRABEAM and Axxent machines with nominal energies of 40 and 50 kV, simulated by GEANT4 toolkit, were employed for RBE assessments. Scored X-ray spectra for each studied machine were used to calculate the corresponding secondary electron spectra at various depths and nominal energies inside the water. Then, Monte Carlo damage simulation (MCDS) code was employed to calculate the initial DNA damages (single and double-strand breaks (SSB and DSB)) and relevant RBE values. Results showed that the scored X-ray spectra for Axxent and INTRABEAM machines are different, a fact which can affect the RBE values for these machines. RBESSB values for Axxent machine were higher than those of INTRABEAM up to 1.4%. In return, RBEDSB values for INTRABEAM machine were greater than Axxent ones up to 4.1%. The obtained RBE values for both machines had a strong and weak dependency on depth and energy, respectively. It can be concluded that the RBE values for studied IORT machines would be different at the same clinical conditions, an issue which can influence the prescribed dose according to the type of employed IORT machine.
In this editorial, we have analyzed the historical evolution of rectal and breast cancer surgery, focusing on the progressive reduction of demolitive approaches and the increasing use of more conservative strategies, accompanied by a growing emphasis on perioperative treatments aimed at enhancing surgical outcomes. All of these changes have been made possible due to an increased awareness and understanding of oncological diseases and improved perioperative treatments.
Background
Intraoperative radiotherapy (IORT) is an alternative for external beam radiotherapy (EBRT) for early stage breast cancer (BC). Herein, we compared outcomes, postoperative and post‐radiation complications of IORT and EBRT.
Methods
We conducted a cohort study to compare complications of IORT and EBRT in patients. A checklist of the complications of IORT and EBRT, was used to assess and post‐radiation complications and outcomes.
Results
Overall, 264 women (121 in IORT and 143 in EBRT group) with a mean (SD) age of 55 ± 8.6 years analyzed in this study. The IORT group (quadrantectomy + SLNB + IORT) had more severe post‐operative pain compared to the EBRT group (quadrantectomy + SLNB) (OR = 1.929, 95% CI: 1.116–3.332). Other postoperative complications, including edema, erythema, seroma, hematoma, and wound complications were not significantly different between the IORT and EBRT groups.
EBRT was associated with higher rates post‐radiation complications, including erythema (95.8% vs. 21.5%), skin dryness (30.8% vs. 12.4%), pruritus (26.6% vs. 17.4%), hyperpigmentation (48.3% vs. 9.9%), and telangiectasia (1.4% vs. 0.8%). Multivariate analysis showed that erythema, skin dryness and pruritus, and hyperpigmentation were more severe in the EBRT group, while breast induration was higher in the IORT group (OR = 4.109, 95% CI: 2.242–7.531). Excellent, good, and fair cosmetic outcome was seen in 11.2%, 72%, and 16.8% of the patients in the EBRT group and 29.8%, 63.6%, and 6.6% in the IORT group, respectively, suggesting that the cosmetic outcome was significantly better in the IORT group (P < .001). There wasn't statistically significant difference in recurrence‐free survival and overall survival rates between two groups of patients who received either IORT or EBRT (P = .953, P = .56).
Conclusion
IORT is considered to have lower post‐radiation complications and better cosmetic outcomes in breast cancer patients. Therefore, IORT might be used as the treatment of choice in eligible patients.
Breast cancer is in the first place in the global structure of the women cancer incidence. Radiation therapy is one of the methods in the treatment of breast cancer. This article focuses on one type of radiation therapy - intraoperative radiation therapy. The data on the experience of using this method of treatment is published.
Purpose/objective
Adjuvant whole breast radiotherapy and systemic therapy are part of the current evidence-based treatment protocols for early breast cancer, after breast-conserving surgery. Numerous randomized trials have investigated the therapeutic effects of partial breast irradiation (PBI) compared to whole breast irradiation (WBI), limiting the treated breast tissue. These trials were designed to achieve equal control of the disease with possible reduction in adverse events, improvements in cosmesis and quality of life (QoL). In this meta-analysis, we aimed to investigate the differences between PBI and WBI in side effects and QoL.
Material/methods
We performed a systematic literature review searching for randomized trials comparing WBI and PBI in early-stage breast cancer with publication dates after 2009. The meta-analysis was performed using the published event rates and the effect-sizes for available acute and late adverse events. Additionally, we evaluated cosmetic outcomes as well as general and breast-specific QoL using the EORTC QLQ-C30 and QLQ-BR23 questionnaires.
Results
Sixteen studies were identified (n = 19,085 patients). PBI was associated with a lower prevalence in any grade 1 + acute toxicity and grade 2 + skin toxicity (OR = 0.12; 95% CI 0.09–0.18; p < 0.001); (OR = 0.16; 95% CI 0.07–0.41; p < 0.001). There was neither a significant difference in late adverse events between the two treatments, nor in any unfavorable cosmetic outcomes, rated by either medical professionals or patients. PBI-technique using EBRT with twice-daily fractionation schedules resulted in worse cosmesis rated by patients (n = 3215; OR = 2.08; 95% CI 1.22–3.54; p = 0.007) compared to WBI. Maximum once-daily EBRT schedules (n = 2071; OR = 0.60; 95% CI 0.45–0.79; p < 0.001) and IORT (p = 0.042) resulted in better cosmetic results grade by medical professionals. Functional- and symptom-based QoL in the C30-scale was not different between PBI and WBI. Breast-specific QoL was superior after PBI in the subdomains of “systemic therapy side effects” as well as “breast-” and “arm symptoms”.
Conclusion
The analysis of multiple randomized trials demonstrate a superiority of PBI in acute toxicity as well breast-specific quality of life, when compared with WBI. Overall, late toxicities and cosmetic results were similar. PBI-technique with a fractionation of twice-daily schedules resulted in worse cosmesis rated by patients.
Introduction
Precision Breast IORT (PB-IORT) is a novel method of intraoperative radiation therapy (IORT) utilizing customized, computed tomography (CT)-based treatment plans and high-dose-rate (HDR) brachytherapy. We conducted a phase II multi-institution trial to evaluate the efficacy of PB-IORT.
Study Design
Between 2015 and 2022, three centers enrolled 358 women aged ≥ 45 with invasive or in situ carcinoma measuring 3 cm or smaller and N0 status. Breast-conserving surgery (BCS) was performed, and a multi-lumen balloon catheter was placed in the lumpectomy bed. CT images were used to create a customized HDR brachytherapy plan delivering 12.5 Gy to the tumor bed. The primary outcome assessed was the 5-year rate of index quadrant tumor recurrence (IQTR). An interim analysis was conducted after one-third of eligible participants completed five years of follow-up. This trial is registered with clinicaltrials.gov (NCT02400658).
Results
The cohort was comprised of 153 participants with a median age of 64 years and a median follow-up time of 5.9 years. The estimated 5-year IQTR rate and overall survival were 5.08% (95% CI 2.23-9.68%) and 95.1%, respectively. Loco-regional (ipsilateral breast and axilla) and distant recurrence rates were each 1.96%. Seven deaths occurred during the first five years of follow-up, with only one attributable to breast cancer. Overall, 68.6% of patients experienced any adverse effects, and four cases of breast-related severe toxicities were observed.
Conclusions
This study presents the results of a planned interim analysis of a Phase II trial investigating PB-IORT and demonstrates the efficacy and safety of single-fraction, CT-based, HDR brachytherapy following BCS. These findings provide valuable insights into utilizing PB-IORT as a treatment modality.
The practice of boost to the tumor bed after treatment with oncoplastic breast-conserving surgery (BCS) remains variable. Using a survey, the present study evaluated the current practice of tumor bed boost administered in women after oncoplastic BCS. Actively practicing radiation oncologists across India were sent a questionnaire on the practice of adjuvant whole-breast radiotherapy and tumor bed boost after oncoplastic BCS via email and encouraged to participate. Of the 54 radiation oncologists who participated, most (98.1%) used a linear accelerator for radiotherapy. Hypofractionation was preferred by 59.26%, standard fractionation by 7.41%, and the remaining selected the fractionation strategy based on various patient factors. In addition, 83.33% participants reported that they always planned tumor boost, 51.85% preferred photons for the boost, and 75.93% administered sequential boost. The most common dose for the boost was 12.5 Gy in five fractions (40.74%). Most participants (77.78%) revealed that they used a combination of methods for identifying the tumor bed. With respect to clip placement, most surgeons (96%) at the participants’ centers placed ≥ 4 clips at the tumor site, with both the base and margins being preferred by surgeons (81.48%) for placement. Finally, 12.96% participants revealed that the surgeons always involved them during surgical planning, whereas 7.4% participants reported that they always included the surgeons during radiotherapy planning, suggesting that radiation oncologists and oncoplastic surgeons do not involve each other during surgical and radiotherapy planning, possibly leading to suboptimal treatment. This may be attributed to the absence of guidelines regarding boost practices after oncoplastic BCS.
External boost radiotherapy (EBRT) and intraoperative radiotherapy (IORT) are shown to be effective in patients with early-stage breast cancer. However, the difference between IORT and EBRT for patients’ prognosis remains to be elucidated. The purpose of this meta-analysis is to investigate differences in local recurrence (LR), distant metastases, disease free survival (DFS), and overall survival (OS) between these two therapies. We searched the Cochrane Library, PubMed, Web of Science and Embase, from inception to Jan 10th, 2022. We used The Cochrane risk-of-bias assessment tool to assess the risk of bias of the included studies, and the STATA15.0 tool was used for the meta-analyses. Eight studies were ultimately included. Meta-analysis demonstrated that there was an inconsistent finding in the long-term risk of LR between the two radiotherapies, and there was no significant difference in short-term risk of LR, the metastasis rate, DFS, and OS IORT would be more convenient, less time-consuming, less costly, and more effective at reducing side effects and toxicity. However, these benefits must be balanced against the potential for increased risk of LR in the long term.
Overview
Breast cancer in women remains a major medical problem with significant public health and societal ramifications, including issues related to screening, risk factors, prevention, diagnosis, treatment, and survival following diagnosis. Major advances have markedly improved the understanding of clinical phenotypes, as well as the biologic pathways that drive tumor growth and resistance. This research has led to dramatic changes in treatment that have contributed to a significant reduction in breast cancer mortality over the last two decades, and is the basis of ongoing clinical research. Molecular profiling has provided insights into the heterogeneity of breast cancer subtypes; combining biology and tumor burden has allowed stratification of both risk and treatment to begin the process of individualizing screening, prevention, and treatment. As new information accumulates, new paradigms of management become the standard of care reflected in international guidelines. Our challenge is to apply new formation and treatment appropriately and effectively, and to understand both response and resistance. Information obtained from molecular, biologic, and pathologic investigations and clinical trials provides the major focus of this chapter.
Purpose
To describe and analyze major local complications after intraoperative radiotherapy (IORT) with low-energy x‑rays during breast-conserving surgery (BCS) in early breast cancer.
Methods
Ten women out of 408 who were treated with IORT between 2002 and 2017 and subsequently developed a severe local complication requiring surgical intervention were retrospectively identified and analyzed. Demographic, clinical, and surgical parameters as well as complication characteristics and treatment methods were evaluated.
Results
At initial presentation, eight patients (80%) showed redness, six (60%) seroma, six (60%) wound infection, six (60%) suture dehiscence, and four (40%) induration of the former surgical area. Hematoma and necrosis were observed in one case (10%) each. Time interval until appearance of the first symptoms ranged from directly postoperative until 15 years postoperatively (median 3.1 months). Initial treatment modalities comprised antibiotic therapy (n = 8/80%) and transcutaneous aspiration of seroma (n = 3/30%). In the majority of patients, smaller surgical interventions (excision of a necrotic area/fistula [n = 6/60%] or secondary suture [n = 5/50%]) were sufficient to overcome the complication, yet larger interventions such as complex flap surgery and mastectomy were necessary in one patient each.
Conclusion
IORT is an efficient and safe treatment method as < 2.5% of all IORT patients experienced major local complications. However, it seems to pose the risk of causing severe local complications that may require lengthy and burdensome treatment. Thorough preoperative counseling, implementation of recommended intraoperative precautions, and high vigilance for first symptoms of complications during follow-up appointments are necessary measures.
In the present study, Monte Carlo (MC) simulation and analytical calculation methods were used to investigate the potential of cancer treatment for the combination of IORT with nanoparticles (NPs). The Geant4 MC toolkit was used to simulate ZEISS INTRABEAM® IORT machine and its smallest applicator with 1.5 cm diameter. The dose enhancement effects (DEFs) were obtained for silver (Ag), gold (Au), bismuth (Bi), copper (Cu) and iron (Fe) spherical NPs considering different concentrations. In addition, analytical calculations were performed based on attenuation coefficient formula for sample NPs. Our MC results showed that the use of different NPs led to an increase in DEF up to 40%. Among different NPs, Au had the maximum DEF. In addition, analytical calculations revealed a significant increase, using NPs as well. Our study has suggested that the use of NPs in combination with IORT has the potential to enhance treatment outcomes.
Background:
Early stage-breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial breast irradiation (PBI) compared with whole breast irradiation (WBI).
Methods:
A systematic review was completed to identify relevant randomized clinical trials (RCTs) and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs).
Results:
14 RCTs and 6 comparative observational studies with 17,234 patients evaluated the comparative effectiveness of PBI. PBI was not significantly different from WBI for IBR at 5 years (RR 1.34 [95% CI, 0.83-2.18]; high strength of evidence [SOE]) and 10 years (RR 1.29 [95% CI, 0.87-1.91]; high SOE). Evidence for cosmetic outcomes was insufficient. Significantly fewer acute AEs were reported with PBI compared to WBI, with no significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and >10 years (high SOE) compared to WBI.
Conclusions:
Ipsilateral breast recurrence was not significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectivness of PBI among selected patients with early-stage, favorable risk breast cancer who are similar to those represented in the included studies.
Background In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. Methods Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor–node–metastasis classification), estrogen-receptor–positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer–specific survival, the time to distant metastasis, and overall survival. Results The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant...
Background in early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995. Methods Information was available on 42 000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23 500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (<10%, 17 000 women; >10%, 25 000 women). Findings About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. Among the 25 000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44.6% versus 49.5% (absolute reduction 5.0%,SE 0.8, 2p<0.00001). These 25 000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1 % (reduction 5.4%, S E 1.3, 2p=0.0002; overall mortality reduction 4.4%, S E 1.2, 2p=0.0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0 06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004). Interpretation In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.
s: Thirty-Second Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 10‐13, 2009; San Antonio, TX
Background : In 1998 we started a phase II study of TARGeted Intraoperative radioTherapy (Targit) using the Intrabeam™ system. We present the updated results of this first group of breast cancer patients treated with breast conserving surgery where Targit was used as a boost to the tumour bed. Patients and Method : We treated 300 cancers in 299 patients undergoing breast-conserving surgery with no other selection criteria. 32% of the patients were younger than 51 years, 57% of cancers were between 1 to 2cm, (21% > 2cm), 29% had a grade 3 tumour and 29% were node positive. After lumpectomy, a single dose of 20Gy was delivered intraoperatively using 50 kV X-rays –calculated at the surface of the tumour bed1. In all except 9 patients Targit was delivered at the time of the lumpectomy. Postoperative external beam radiotherapy excluded the usual boost. We analyzed recurrences according to their position within the ipsilateral breast. Results: The treatment was well tolerated. The median follow up is 60.5 months (range 10-120 months). 8 patients have had ipsilateral recurrence: 5- year Kaplan Meier estimate for ipsilateral recurrence 1.74% (SE 0.77). 5 of these 8 patients had recurrence in the tumor bed: 5-year Kaplan Meier recurrence rate is 1.04% (SE 0.59). Additionally, 7 patients developed a contralateral breast cancer. Our results appear superior to those seen in the boosted patients in the EORTC study (4.3%) and the START-B study (2.8%) despite a higher node positivity in our series (29%), compared with 21% in the EORTC and 24% in the START-B trial and a larger proportion of younger women (<50 were 32% in Targit, 37% in EORTC and 21% in START-B). Conclusion: Lumpectomy and Targit boost combined with external beam radiotherapy results in an exceptionally low tumor bed recurrence rate in an unselected patient population. This could be attributed to both accurate localisation and timeliness of the treatment that could have a favorable effect on tumour micro-environment2. When used as a boost Targit is likely to be superior to conventional external boost. These data establish the long-term safety and efficacy of the Targit technique, which is being used in the soon to be completed randomised TARGIT trial of partial breast irradiation vs conventional external beam whole breast radiotherapy.1. Vaidya JS, Baum M, Tobias JS, Morgan S, D'Souza D. The novel technique of delivering targeted intraoperative radiotherapy (Targit) for early breast cancer. Eur J Surg Oncol 2002;28(4):447-54.2. Belletti B, Vaidya JS, D'Andrea S, Entschladen F, Roncadin M, Lovat F, et al. Targeted Intraoperative radiotherapy (TARGIT) impairs surgical wound-stimulated breast cancer cell proliferation and invasion Clin.Cancer Res. 2008;14(5):1325-32.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4104.
Introduction:
We believe that conservative treatment of early breast cancer may not require radiotherapy that encompasses the whole breast. We present here the clinico-pathological basis for this view, as well as a novel therapeutic approach that allows intra-operative radiotherapy to be safely and accurately delivered to the target tissues in a standard operating theatre. THE RATIONALE: Whole-organ analysis of mastectomy specimens reveals that 80% of occult cancer foci are situated remote from the index quadrant. In contrast, over 90% of local recurrences after breast conservative therapy occur near the original tumour, even when radiotherapy is not given. Therefore, the remote occult cancer foci may be clinically irrelevant and radiotherapy to the index quadrant alone might be sufficient. A NOVEL TECHNIQUE: The Photon Radiosurgery System (PRS) is an ingenious portable electron-beam driven device that can typically deliver intra-operative doses of 5-20 Gy, respectively, to 1 cm and 0.2 cm from the tumour bed over about 22 min. The pliable breast tissue--the target--wraps around the source, providing perfect conformal radiotherapy. Being soft X-rays, the dose attenuates rapidly (alpha approximately 1/r3), reducing distant damage.
Results:
In our pilot study of 25 patients (age 30-80 years, T = 0.42-4.0 cm), we replaced the routine post-operative tumour bed boost with targeted intra-operative radiotherapy. There have been no major complications and no patient has developed local recurrence, although the median follow-up time is short, at 24 months.
Conclusion:
It is safe and feasible to deliver targeted intraoperative radiotherapy (Targit) for early breast cancer. We have begun a randomised trial--the first of its kind--comparing Targit with conventional six-week course of radiotherapy. If proven equivalent in terms of local recurrence and cosmesis, it could eliminate the need for the usual six-week course of post-operative radiotherapy.
To determine if the length of interval between breast conserving surgery and start of radiotherapy affects local recurrence and to identify factors that might be associated with delay in older women with breast cancer.
Retrospective cohort analysis with Cox proportional hazards models to study the association between time to radiotherapy and local recurrence, and propensity score and instrumental variable analyses to confirm findings. Logistic regression investigated factors associated with later start of radiotherapy.
Linked database (Surveillance, Epidemiology, and End Results Program-Medicare) in the United States
18 050 women aged over 65 with stage 0-II breast cancer diagnosed in 1991-2002 who received breast conserving surgery and radiotherapy but not chemotherapy.
Local recurrence.
Median time from surgery to start of radiotherapy was 34 days, with 29.9% (n=5389) of women starting radiotherapy after six weeks. Just over 4% (n=734) of the cohort experienced a local recurrence. After adjustment for clinical and sociodemographic factors, intervals over six weeks were associated with increased likelihood of local recurrence (hazard ratio 1.19, 95% confidence interval 1.01 to 1.39, P=0.033). When the interval was modelled continuously (assessing accumulation of risk by day), the effect was statistically stronger (hazard ratio 1.005 per day, 1.002 to 1.008, P=0.004). Propensity score and instrumental variable analysis confirmed these findings. Instrumental variable analysis showed that intervals over six weeks were associated with a 0.96% increase in recurrence at five years (P=0.026). In multivariable analysis, starting radiotherapy after six weeks was significantly associated with positive nodes, comorbidity, history of low income, Hispanic ethnicity, non-white race, later year of diagnosis, and residence outside the southern states of the US.
There is a continuous relation between the interval from breast conserving surgery to radiotherapy and local recurrence in older women with breast cancer, suggesting that starting radiotherapy as soon as possible could minimise the risk of local recurrence. There are considerable disparities in time to starting radiotherapy after breast conserving surgery. Regions of the US known to have increased rates of breast conserving surgery had longer intervals before radiotherapy, suggesting limitations in capacity. Given the known negative impact of local recurrence on survival, mechanisms to ameliorate disparities and policies regarding waiting times for treatment might be warranted.
Radiotherapy of the left breast is associated with higher cardiovascular mortality linked to cardiotoxic effect of irradiation. Radiotherapy of inner quadrants can be associated with greater heart irradiation, but no study has evaluated the effect of inner-quadrant irradiation on cardiovascular mortality.
We identified 1245 women, the majority with breast-conserving surgery, irradiated for primary node-negative breast cancer from 1980 to 2004 registered at the Geneva Cancer Registry. We compared breast cancer-specific and cardiovascular mortality between inner-quadrant (n = 393) versus outer-quadrant tumors (n = 852) by multivariate Cox regression analysis.
After a mean follow-up of 7.7 years, 28 women died of cardiovascular disease and 91 of breast cancer. Patients with inner-quadrant tumors had a more than doubled risk of cardiovascular mortality compared with patients with outer-quadrant tumors (adjusted hazard ratio 2.5; 95% confidence interval 1.1-5.4). Risk was particularly increased in the period with higher boost irradiation. Patients with left-sided breast cancer had no excess of cardiovascular mortality compared with patients with right-sided tumors.
Radiotherapy of inner-quadrant breast cancer is associated with an important increase of cardiovascular mortality, a possible result of higher irradiation of the heart. For patients with inner-quadrant tumors, the heart should be radioprotected.
To explain bimodal relapse patterns observed in breast cancer data, we have proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. The half-lives of these states are 1 and 2 years respectively. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from early detection, through treatment and follow-up, and consider how dormancy and surgery-driven escape from dormancy would be observed. We examine mammography data, effectiveness of adjuvant chemotherapy, heterogeneity and aggressiveness, timing of surgery within the menstrual cycle and racial differences in outcome. Dormancy can be identified in these diverse data but most conspicuous is the sudden escape from dormancy following primary surgery. These quantitative findings provide linkage between experimental studies of tumor dormancy and clinical efforts to improve patient outcome.
One thousand two hundred and thirty-two women with invasive breast cancer lesions measuring less than 2 cm in diameter, clinically assessed as T1N0-1M0, were treated from 1970 to 1983 at the National Cancer Institute of Milan with quadrantectomy, axillary dissection, and radiotherapy (QUART). Pathologic evidence of lymph-nodes metastases was found in 32% of the patients. Overall survival at 5 and 10 years from surgery was 91% and 78%, respectively. The cumulative probability of survival tends to decrease with increasing tumor size: the 7-year survival rate was 84% in cases in which lesions measured from 1.6 to 2.0 cm, and 94% in cases in which the lesions were less than 0.5 cm. Tumor site in the treated breast did not affect distant outcome. No difference was found between the patients without node metastases and patients with one node involved, whereas the patients with more than one node showed a lower probability of survival. The survival curves of 352 cases treated inside a randomized trial and that of 880 cases routinely treated appear to be superimposable. Local recurrences and new primary ipsilateral tumors were, respectively, 35 (2.8%) and 19 (1.6%); 56 women with local recurrences or second tumors underwent second surgery (total mastectomy, 43; wide resection, 11). Five of them died from distant spread of breast cancer, while 49 are alive and well. In the contralateral breasts 45 carcinomas were recorded during the follow-up time. The results of the present analysis of a large number of T1 cases reconfirm the safety of integrated radiosurgical conservative treatments.
Previous findings from a clinical trial (Protocol B-06) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) indicated the worth of lumpectomy and breast irradiation for treating breast cancer. After the discovery by NSABP staff members of falsified information on patients enrolled in the study by St. Luc Hospital in Montreal, separate audits were conducted at St. Luc Hospital and other participating institutions. We report the results of both audits and update the study findings through an average of 12 years of follow-up.
Patients with either negative or positive axillary nodes and tumors 4 cm or less in diameter were randomly assigned to one of three treatments: total mastectomy, lumpectomy followed by breast irradiation, or lumpectomy without irradiation. Three cohorts of patients were analyzed. The first cohort included all 2105 randomized patients, who were analyzed according to the intention-to-treat principle. The second cohort consisted of 1851 eligible patients in the first cohort with known nodal status who agreed to be followed and who accepted their assigned therapy (among those excluded were 6 patients from St. Luc Hospital who were declared ineligible because of falsified biopsy dates). The third cohort consisted of the patients in the second cohort minus the 322 eligible patients from St. Luc Hospital (total, 1529 patients).
Regardless of the cohort, no significant differences were found in overall survival, disease-free survival, or survival free of disease at distant sites between the patients who underwent total mastectomy and those treated by lumpectomy alone or by lumpectomy plus breast irradiation. After 12 years of follow-up, the cumulative incidence of a recurrence of tumor in the ipsilateral breast was 35 percent in the group treated with lumpectomy alone and 10 percent in the group treated with lumpectomy and breast irradiation (P < 0.001).
Our findings continue to indicate that lumpectomy followed by breast irradiation is appropriate therapy for women with either negative or positive axillary nodes and breast tumors 4 cm or less in diameter.
We studied the spatial relationship within the breast between multicentric foci (MCF) and the primary tumour in 30 modified radical mastectomy specimens using Egan's correlated pathological-radiological method using 5 mm slices of the whole breast. The relative positions within the breast of the primary tumour and MCF were used to calculate the relative distribution of primary tumour and MCF in the four quadrants of the breast and the per cent breast volume that would be required to be excised to include all MCF. Nineteen (63%) breast harboured MCF. The relative distribution of primary tumour and MCF in the four breast quadrants was significantly different (P = 0.034). MCF were present beyond the index quadrant (25% of breast volume including the tumour) in as many as 79% (15/19) of breasts that harboured MCF; and in half the cases (15/30) when all breast were considered. This is in variance with the suggestion put forward previously that MCF are contained within the index quadrant in 90% of cases. Although the number of patients in the present series is small, the probability of our finding being due to play of chance is 1 in 1500. In a large series of breast conservation studies > 90% of early breast recurrences have been found to occur in the index quadrant. Our finding, that in half the patients (15/30) MCF are present in quadrants other than the index quadrant, suggests that MCF do not give rise to early breast recurrence.
The adequate timing of adjuvant radiotherapy (RT) in breast cancer has become a subject of increasing interest in recent years. A population-based study was undertaken to determine the influence of demographic and clinical factors on the postoperative RT delay in patients treated with breast-conserving surgery (BCS) and to assess the impact of delay on survival. In total, 7800 breast cancer patients treated with BCS and adjuvant RT between 1986 and 1998 in Yorkshire were included in the study. The median interval between surgery and the start of RT (S-RT interval) was 8 weeks (7 weeks for chemotherapy negative and 11 for chemotherapy positive patients). This interval increased substantially over time from 5 weeks during 1986-1988, irrespective of patients' chemotherapy status, to 10 and 17 weeks among chemotherapy negative and chemotherapy positive patients, respectively, in 1997-1998. The S-RT interval was also significantly influenced by travel time to RT centre, year and at which RT centre patient had the treatment (P<0.001). Overall, 5-year survival was 82%. Patients with S-RT intervals longer than 9 weeks had a trend towards an increased relative risk of death. This reached a statistical significance at 20-26 weeks (RR 1.49, 95% CI (1.16-1.92)). The findings of our study suggest that delaying the initiation of RT for 20-26 weeks after surgery is associated with decreased survival in patients treated with conservation surgery.
In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy.
Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor-node-metastasis classification), estrogen-receptor-positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer-specific survival, the time to distant metastasis, and overall survival.
The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone.
Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer.
We determined the effect of breast irradiation plus tamoxifen on disease-free survival and local relapse in women 50 years of age or older who had T1 or T2 node-negative breast cancer.
Between December 1992 and June 2000, 769 women with early breast cancer (tumor diameter, 5 cm or less) were randomly assigned to receive breast irradiation plus tamoxifen (386 women) or tamoxifen alone (383 women). The median follow-up was 5.6 years.
The rate of local relapse at five years was 7.7 percent in the tamoxifen group and 0.6 percent in the group given tamoxifen plus irradiation (hazard ratio, 8.3; 95 percent confidence interval, 3.3 to 21.2; P<0.001), with corresponding five-year disease-free survival rates of 84 percent and 91 percent (P=0.004). A planned subgroup analysis of 611 women with T1, receptor-positive tumors indicated a benefit from radiotherapy (five-year rates of local relapse, 0.4 percent with tamoxifen plus radiotherapy and 5.9 percent with tamoxifen alone; P<0.001). Overall, there was a significant difference in the rate of axillary relapse at five years (2.5 percent in the tamoxifen group and 0.5 percent in the group given tamoxifen plus irradiation, P=0.049), but no significant difference in the rates of distant relapse or overall survival.
As compared with tamoxifen alone, radiotherapy plus tamoxifen significantly reduces the risk of breast and axillary recurrence after lumpectomy in women with small, node-negative, hormone-receptor-positive breast cancers.
The purpose of this study was to model the distribution of biological effect around a miniature isotropic X-ray source incorporating spherical applicators for single-dose or hypo-fractionated partial-breast intraoperative radiotherapy. A modification of the linear-quadratic formalism was used to calculate the relative biological effectiveness (RBE) of 50 kV X rays as a function of dose and irradiation time for late-reacting normal tissue and tumor cells. The response was modeled as a function of distance in the tissue based on the distribution of equivalent dose and published dose-response data for pneumonitis and subcutaneous fibrosis after single-dose conventional irradiation. Furthermore, the spatial distribution of tumor cell inactivation was assessed. The RBE for late reactions approached unity at the applicator surface but increased as the absorbed dose decreased with increasing distance from the applicator surface. The ED50 for pneumonitis was estimated to be reached at a depth of 6-11 mm in the tissue and that for subcutaneous fibrosis at 3-6 mm, depending on the applicator diameter and whether the effect of recovery was included. Thus lung tissue would be spared because of the thickness of the thorax wall. The RBE for tumor cells was higher than for late-reacting tissue. The applicator diameter is an important parameter in determining the range of tumor cell control in the irradiated tumor bed.
Jayant S, VaidyaDavid J, JosephJeffrey S, TobiasMax, BulsaraFrederik, WenzChristobel, SaundersMichael, AlvaradoHenrik L, FlygerSamuele, MassarutWolfgang, EiermannMohammed, KeshtgarJohn, DewarUta, Kraus-TiefenbacherMarc, SütterlinLaura, EssermanHelle MR, HoltvegMario, RoncadinSteffi, PigorschMarinos, MetaxasMary, FalzonApril, MatthewsTammy, CoricaNorman R, WilliamsMichael, Baum. (2010) Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. The Lancet 376, 91-102
CrossRef
Pathologic review of 861 Stage I and II breast cancers yielded 152 patients (18%) with histologic types other than invasive ductal carcinoma. All patients had been treated by breast-conserving surgery and radiotherapy, including supplemental radiation to the tumor bed. For 67 patients with predominantly lobular carcinomas, the actuarial overall 5-year survival was 100% and 77% for node-negative and node-positive patients, respectively. The actuarial probability of recurrence in the treated breast (13.5% at 5 years) appeared to be somewhat greater than that observed after treatment of invasive ductal cancers (8.8% at 5 years, P = 0.11). Of 12 mammary recurrences in patients with lobular carcinoma, four occurred at a considerable distance from the original primary and seven were multifocal, involving more than one quadrant in five patients. Of 47 patients with strictly in situ carcinomas, one patient whose axillary nodal status had not been determined subsequently developed distant metastases. Three additional patients developed mammary recurrence, two at the primary tumor site and one in another quadrant. The actuarial 5-year mammary recurrence and overall survival rates were 4% and 98%, respectively. For 27 patients with true medullary cancers, overall survival at 5 years was 90%. One localized mammary recurrence was observed at the site of the original primary. Actuarial mammary recurrence rate was 4% at 5 years. No relapse was observed in ten patients with colloid and one patient with adenoid cystic carcinoma. The authors conclude that, in addition to its well-established efficacy in the treatment of infiltrating ductal carcinomas, the combination of tumor excision and radiotherapy appears to provide adequate local control for other histologic types as well. However, patients with lobular cancer appear to be at somewhat greater risk of mammary failure, and recurrences in such patients tend to be multifocal and multicentric.
Early local recurrence of breast cancer most commonly (over 90%) occurs at the site of the primary tumour. This is true whether or not radiotherapy is given and irrespective of the margin status.
Whole-organ analysis of mastectomy specimens on the other hand, reveals that 63% of breasts harbour occult
cancer foci and 80% of these are situated remote from the index quadrant. Therefore, these occult cancer foci may be clinically irrelevant and it may not be necessary to treat the whole breast with radiotherapy. This 6-wks long
course of post-operative radiotherapy after breast conserving therapy is not only inconvenient and costly, but
may cause many women from geographically remote areas to
choose mastectomy. Targeted Intraoperative radiotherapy
(TARGIT) to the peri-tumoural area alone might provide adequate local control. ‘Intrabeam’ (PeC) is a
portable electron-beam driven device that can deliver therapeutic radiation (soft x-rays) in 20-30 minutes within
a standard operating theatre environment. The pliable breast
tissue - the target - is wrapped around a spherical applicator - the source - providing truly conformal
radiotherapy. The prescribed dose is 5 & 20Gy at 1cm and 0.2cm respectively, from the tumour bed. The biologically
effective dose is 7-53Gy for α/β=10 and 20-120Gy for α/β=1.5. In our pilot study of 26 patients (age 30-80 years,
T=0.42-4.0cm), we replaced the routine post-operative tumour bed boost with targeted intra-operative radiotherapy.
There have been no major complications and no patient has
developed local recurrence, although the median follow-up time is short at 34 months. The cosmetic outcome is
satisfying to both the patient and the clinician. Having established the feasibility, acceptability and safety in
the pilot study, we started in March 2000, a randomised trial that compares TARGIT with conventional postoperative
radiotherapy for infiltrating duct carcinomas, with local recurrence and cosmesis as the main outcome measures. Patient accrual in this trial has been excellent and it has attracted several international collaborative groups. If proven effective, TARGIT could eliminate the need for postoperative radiotherapy potentially saving time, money and breasts.
The year 2008 marked another eventful year for Cancer Research. Some of the many significant achievements of 2008 included the receipt of nearly 5,000 new submissions; the addition of Deputy Editors, who are contributing to the strategic vision of the journal; and publication of outstanding papers
Accelerated partial breast radiotherapy with low-energy photons from a miniature X-ray machine is undergoing a randomized clinical trial (Targeted Intra-operative Radiation Therapy [TARGIT]) in a selected subgroup of patients treated with breast-conserving surgery. The steep radial dose gradient implies reduced tumor cell control with increasing depth in the tumor bed. The purpose was to compare the expected risk of local recurrence in this nonuniform radiation field with that after conventional external beam radiotherapy.
The relative biologic effectiveness of low-energy photons was modeled using the linear-quadratic formalism including repair of sublethal lesions during protracted irradiation. Doses of 50-kV X-rays (Intrabeam) were converted to equivalent fractionated doses, EQD2, as function of depth in the tumor bed. The probability of local control was estimated using a logistic dose-response relationship fitted to clinical data from fractionated radiotherapy.
The model calculations show that, for a cohort of patients, the increase in local control in the high-dose region near the applicator partly compensates the reduction of local control at greater distances. Thus a "sphere of equivalence" exists within which the risk of recurrence is equal to that after external fractionated radiotherapy. The spatial distribution of recurrences inside this sphere will be different from that after conventional radiotherapy.
A novel target volume concept is presented here. The incidence of recurrences arising in the tumor bed around the excised tumor will test the validity of this concept and the efficacy of the treatment. Recurrences elsewhere will have implications for the rationale of TARGIT.
Although the conservation management of breast cancer has become a routine method of treatment in most centers, there is still considerable controversy surrounding the ultimate minimum treatment required for node-negative breast cancer to achieve adequate local control.
Our purpose was to assess the value of breast irradiation in reducing breast relapse following conservation surgery for node-negative breast cancer. We attempted to define low-risk groups of women for breast and distant site relapse (i.e., recurrence outside the breast) who might be spared breast irradiation or adjuvant systemic therapy.
Eight hundred thirty-seven patients were randomly assigned to receive radiation therapy or no radiation therapy following lumpectomy and axillary dissection for node-negative breast cancer.
Breast irradiation reduced relapse in the breast from 25.7% in the controls to 5.5% in the irradiated patients. There was no difference in survival between the two groups (median follow-up, 43 months). A low-risk group (less than 5% chance of relapse in the breast without irradiation) could not be defined. Tumor size (greater than 2 cm), age (less than 40 years), and poor nuclear grade were important predictors for breast relapse. Age (less than 50 years) and poor nuclear grade were important predictors for mortality. The presence of ductal carcinoma in situ did not predict breast relapse.
Breast irradiation significantly reduces breast relapse, but it does not influence survival. Important predictors of breast relapse are age, tumor size, and nuclear grade, but not the presence of ductal carcinoma in situ. Age and, in particular, nuclear grade predict survival.
Further follow-up may define an acceptable low-risk group for breast relapse. Until then, we recommend that all patients receive breast irradiation. Systemic adjuvant therapy should be considered for patients with poor nuclear grade tumors.
Ipsilateral breast tumor recurrence (IBTR) occurred in 42 of 488 (9%) pathologically evaluable patients enrolled in NSABP protocol B-06 with a mean potential follow-up of 103 months (range 68-161 months) following treatment for Stage I and II invasive breast cancer by lumpectomy and local breast irradiation (LXRT). IBTR were observed at or close to the same quadrant as the index cancers and their histologic types and nuclear grades were similar if not identical in 95 and 93%, respectively. This information confirms our earlier findings which indicated that multicentricity is of little or no clinical significance in the treatment of breast cancer by LXRT; breast cancers rarely if ever change their biologic potential once clinically detected; and lastly, most if not all IBTR represent residual cancer. Cox regression analyses revealed only a patient age less than 35 years to be significantly related to IBTR. No relationship between IBTR and so-called extensive intraductal component (EIC) or 31 other pathologic features of the index cancers was found. Overall survival was significantly related to nodal status (P = 0.01), nuclear grade (P = less than 0.001) histologic tumor type (P = 0.01) and IBTR (P = less than 0.001). This latter was considered as an indicator rather than instigator of distant disease and reduced survival since the latter is no different in patients treated by LXRT, lumpectomy alone after which IBTR is much more frequent, or mastectomy, which precludes its expression. We conclude that there are as yet no viable markers which would contraindicate treating patients with breast cancer by LXRT.
The identification of factors associated with breast recurrence following conservative surgery (CS) and radiation therapy (RT) is of potential use in refining patient selection criteria and treatment technique. In an attempt to define such factors we examined the relationship between various clinical, pathologic and treatment characteristics and the likelihood of breast recurrence in 783 patients with clinical stage I or II breast cancer treated between July 1968 and December 1982. Treatment consisted of complete gross excision of the primary tumor and RT to a total dose of at least 60 Gy to the primary site. During this period, pre-treatment mammograms and detailed histologic assessment of the margins of resection were not routinely performed. Median follow-up for surviving patients was 80 months. Thirteen patients (1.6%) were lost to follow-up. Ninety-one patients (12%) have developed a breast recurrence, corresponding to 5- and 10-year actuarial rates of 10 and 18%, respectively. The major feature associated with breast recurrence was the presence of an "extensive intraductal component" (EIC+). An EIC+ tumor was seen in 28% of evaluable cases with infiltrating ductal carcinoma and accounted for 60% of breast recurrences. Forty-three of 166 patients (26%) with EIC+ tumors developed a breast recurrence compared with 29 of 418 patients (7%) without an EIC (EIC-) (p = 0.0001). The 5-year actuarial rates of breast relapse were 24 and 6%, respectively (p = 0.0001). Very young age (defined as 34 years of age or younger) was also a significant factor associated with the risk of breast recurrence. Very young patients comprised 8% of the patient population and accounted for 16% of breast recurrences. Fifteen of 61 very young patients (25%) developed a breast recurrence compared with 76 of 722 older patients (11%) (p = 0.001). The corresponding 5-year actuarial rates of breast recurrence were 21 and 9% (p = 0.005). None of the other clinical or pathological factors examined by univariate analysis were significantly correlated with recurrence in the breast. A multivariate model of site of first failure (polychotomous logistic regression) also showed that EIC+ tumors and very young age were the main factors associated with a high relative risk of breast recurrence. We conclude that EIC+ tumors and very young age are associated with a high risk of breast recurrence for patients treated with limited excision prior to RT.
Thirty-four gross and histologic features of the primary tumor in 231 cases of clinical Stage I and II invasive breast cancer were reviewed in an attempt to identify features which might correlate with an increased risk of local recurrence within the breast following biopsy and primary radiation therapy. Local recurrence risk at 5 years was calculated for each feature studied. While results are reported in terms of 5-year actuarial local recurrence risk, not all patients were followed for 5 years (median follow-up period, 44 months). Patients with cases in which the biopsy was less than excisional had a considerably greater actuarial risk of local recurrence at 5 years than those in which the biopsy was excisional (36% versus 8%; P = 0.0005). Among 154 infiltrating ductal carcinomas treated by excisional biopsy prior to radiotherapy, histologic features associated with a significantly increased local recurrence risk at 5 years were the combination of extensive intraductal involvement by carcinoma and high nuclear grade and/or high mitotic index. Twenty-seven tumors demonstrated this constellation of features, and there was a 5-year actuarial local recurrence risk of 39% among this group. The local recurrence risk for the remainder of the population was only 4% (P less than 0.0001). Thus, through pathologic examination of the primary, the authors identified a subgroup of patients with a considerably increased risk of local recurrence following biopsy and primary radiotherapy.
Evidence is presented from a study of 680 patients followed over a period of 21 years that conservative treatment of breast cancer by local excision of the primary tumor followed by breast irradiation yields results equivalent to the traditional radical approach, with the added benefit of an excellent cosmetic result and improved quality of life. The relative survivals were 8.3% at 5 years and 71% at 10 years. There was no difference in survival when radiation was given. Breast irradiation significantly reduced relapse in the breast, but axillary irradiation did not influence relapse at this site. Relapse in the breast alone was not detrimental to survival if treated appropriately. Axillary relapse indicated a much poorer prognosis as might be expected.
Conservative surgery and radiotherapy have become well-established treatments for breast cancer, and many trials in progress are attempting to define the most acceptable type of procedure. Between 1987 and 1989 we randomly assigned 567 women with small breast cancers (< 2.5 cm in diameter) to quadrantectomy followed by radiotherapy or to quadrantectomy without radiotherapy. All patients underwent total axillary dissection. The median follow-up period was 39 months (range, 28 to 54).
The incidence of local recurrence was 8.8 percent among the patients treated with quadrantectomy without radiotherapy, as compared with 0.3 percent among those treated with postsurgical radiotherapy (P = 0.001). However, there was a substantial effect of age: patients more than 55 years old who did not receive radiotherapy had a low rate of local recurrence (3.8 percent). The four-year overall survival was similar in the two treatment groups.
Administering radiotherapy after quadrantectomy reduces the risk of local recurrence in women with small cancers of the breast, but radiotherapy may not be necessary in elderly women.
Several groups are developing ultra-miniature x-ray machines for clinical use in radiation therapy. Current systems are for interstitial radiosurgery and for intravascular insertion for irradiation to prevent re-stenosis. Typical generating voltages are low, in the 20 to 40 kV range. It is well established that the biological effectiveness of such low-energy photons is large compared with higher-energy gamma rays, because of the dominance of photoelectric absorption at low energies. We have used microdosimetric analyses to estimate RBEs for such devices, both at low doses and clinically relevant doses, relative to radiations from 60Co, 192Ir, 125I and 90Sr/90Y. The RBEs at clinically relevant doses and dose rates for these low-energy x-ray sources are considerably above unity, both relative to 60Co and to 192Ir photons, and also relative to 125I and 90Sr/90Y brachytherapy sources. As a function of depth, the overall effect of the change in dose and the change in beam spectrum results in beams whose biologically weighted dose (dose x RBE) decreases with depth somewhat more slowly than does the physical dose. The estimated clinically relevant RBEs are sufficiently large that they should be taken into account during the treatment design stage.
Determine the radiobiological effectiveness (RBE) for low-energy X-rays (average energy of 23 KeV) produced by the Photon Radiosurgery System (PRS).
RBE values were assessed by comparison with survival data obtained for cells irradiated with either low-energy X-rays from a GE Maxitron 100 machine or high-energy photons from a clinically used Varian 6 MV LINAC. The output of the GE and PRS sources was determined using Baldwin-Farmer and Markus thin window ionization chambers calibrated with 50 kVp X-rays and cross-checked against figures supplied by Photoelectron Corporation. The dose-rate for the PRS was 1.2 Gy/min at a distance of 35 mm with a field flatness of +/-2%.
The RBE for the PRS low-energy X-ray source (at 1-mm depth) was greater than either the GE or Varian machines and varied with cell survival. For Chinese hamster ovary (CHO) cells, the PRS was 1.25 and 3.3 times more effective than 90 kVp X-rays and 6 MeV photons at 0.5% cell survival, respectively; by comparison, the PRS was 1.2 and 1.9 times more effective at 0.05% cell survival, respectively. Similar RBE values of 1.4 and 1.2 were obtained for human U373 and T98 glioblastoma cells grown in vitro irradiated with the PRS or GE sources, respectively. Other studies showed that the RBE for the PRS low-energy X-ray source increased with depth. The RBEs for the PRS source at 1-mm and 4-mm depth were 1.2 and 2.5 (0.5% survival) and 1. 2 and 1.9 (0.05% survival).
The biological and physical properties of the PRS low-energy X-rays offer, under the right conditions, a significant advantage for patient treatment over conventional external beam, stereotactic, or brachytherapy treatment.
Survival plots of time-to-event data are a key component for reporting results of many clinical trials (and cohort studies). However, mistakes and distortions often arise in the display and interpretation of survival plots. This article aims to highlight such pitfalls and provide recommendations for future practice. Findings are illustrated by topical examples and also based on a survey of recent clinical trial publications in four major journals. Specific issues are: should plots go up or down (we recommend up), how far in time to extend the plot, showing the extent of follow-up, displaying statistical uncertainty by including SEs or CIS, and exercising caution when interpreting the shape of plots and the time-pattern of treatment difference.
We believe that conservative treatment of early breast cancer may not require radiotherapy that encompasses the whole breast in all patients. We have developed a novel therapeutic approach that allows targeted intraoperative radiotherapy (Targit) to be safely and accurately delivered in a standard operating theatre. We are currently recruiting for a randomized trial testing whether Targit can replace the whole 6 weeks of post-operative radiotherapy after breast conserving surgery.
This paper describes the operative technique. It employs a miniature electron-beam-driven X-ray source called INTRABEAM (PeC) that emits soft X-rays (50 kV) from within the breast. The X-rays are emitted from the tip of a 10 cm x 3.2 mm diameter probe, that is enclosed in a spherical applicator (available in 2.5-5 cm diameter sizes), which in turn is inserted in the tumour bed and intraoperative radiotherapy is delivered in about 25 min. The prescribed dose is 5 and 20 Gy at 1 cm and 0.2 cm respectively, from the tumour bed.
The biologically effective dose is 7-53 Gy for alpha/beta=10 and 20-120 Gy for alpha/beta=1.5. The quick attenuation of the radiation reduces the damage to normal tissues and allows radiotherapy to be delivered in a standard operating theatre. Tungsten impregnated rubber sheets, cut to size, are placed on the chest wall to protect the heart/lungs and over the wound to stop stray radiation. The skin dose is monitored with thermoluminescent detectors (TLDs). After wide local excision of the tumour and good haemostasis, a spherical applicator is inserted in the tumour bed and the target breast tissues are wrapped around it with a purse-string suture. Thus, true conformation of the target around the applicator source is achieved in real time.
As a tumour bed boost, this technique has the potential to reduce local recurrence by avoiding geographical misses and achieving excellent dosimetry. In patients with low risk of local recurrence, it has the potential to replace the full 6 weeks of post-operative radiotherapy with considerable implications to patients and hospitals.
This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of </= 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone.
After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of.05 or less were statistically significant.
XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P =.28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P =.039). Survival in the three groups was 93%, 94%, and 93%, respectively (P =.93).
In women with tumors </= 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.
Local recurrences after breast-conserving surgery occur mostly in the quadrant harbouring primary carcinoma. The main objective of postoperative radiotherapy should be the sterilisation of residual cancer cells in the operative area while irradiation of the whole breast may be avoided. We have developed a new technique of intraoperative radiotherapy of a breast quadrant after the removal of the primary carcinoma (ELIOT). A mobile linear accelerator with a robotic arm is utilised delivering electron beams able to produce energies from 3 to 9 MeV. Different dose levels were tested from 10 to 21 Gy without important side effects. A randomized trial is currently ongoing in order to compare conventional irradiation and ELIOT. More than 400 patients have been enrolled. In addition a new approach for nipple and areola complex conservation, including ELIOT, is under investigation.
A revolution is challenging the dogma that local treatment for all patients with breast cancer treated with breast conservation therapy must include postoperative radiotherapy delivered to the whole breast. Such prolonged postoperative radiotherapy is a burden to patients and hospitals and forces many women to chose mastectomy instead. Furthermore, for patients receiving chemotherapy, the start of conventional radiotherapy may be delayed so long as to increase the risk of local relapse. These problems might be eliminated if effective radiotherapy could be given as a single treatment intraoperatively, immediately after the surgery. Local recurrence after breast-conserving surgery usually occurs in the portion of the breast in the immediate proximity of the tumor, even when radiotherapy is omitted. Therefore, it should usually be possible to restrict radiotherapy to only the area adjacent to the tumor in selected women. Based on this premise, we have devised a new technique of partial breast irradiation, with the intention of completing all local treatment in a single session. In this article, we elaborate on the rationale and on the different methods of delivering intraoperative radiotherapy. If this approach is validated in ongoing randomized trials, it could save time, money, and breasts.
Adjuvant endocrine therapies such as tamoxifen, goserelin, and oophorectomy improve survival for premenopausal women diagnosed with early-stage breast cancer. However, these treatments often result in menopausal symptoms, sexual dysfunction, permanent infertility, or the need to delay pregnancy. We aimed to quantify the survival gains that premenopausal patients with early-stage breast cancer require to justify the side-effects and inconvenience of adjuvant endocrine treatments.
Participants consisted of 102 women who had been diagnosed with early-stage (stage I-II) breast cancer 6-60 months previously, who were aged 40 years or younger at diagnosis, and who had been treated for a minimum of 3 months with endocrine therapy (67 with tamoxifen alone, seven with goserelin alone, and 28 with tamoxifen and goserelin or oophorectomy). 76 patients also received chemotherapy, and 75 received radiotherapy. Participants attended a face-to-face patient-preference interview, in which they were presented with four hypothetical clinical scenarios that were used to quantify the gains in survival rate and life expectancy that women judged necessary to make their endocrine therapy worthwhile. They also completed a questionnaire on standard psychological measures.
About half of participants thought that adjuvant endocrine therapy was worthwhile for an absolute gain in survival of 2% from a baseline of either 65% or 85%, and for a gain in life expectancy of 3 months from a baseline of 5 years and of 6 months for a baseline of 15 years. Women who had had more severe endocrine side-effects required larger gains to make endocrine therapy worthwhile (univariate p=0.02, multivariate p=0.04).
Modest gains in survival are sufficient to make adjuvant endocrine treatment worthwhile for premenopausal women with early-stage breast cancer. Knowing and incorporating what women think should enhance shared decision-making.
High rates of mastectomy and marked regional variations have motivated lingering concerns about overtreatment and failure to involve women in treatment decisions. We examined the relationship between patient involvement in decision making and type of surgical treatment for women with breast cancer.
All women with ductal carcinoma-in-situ and a 20% random sample of women with invasive breast cancer aged 79 years and younger who were diagnosed in 2002 and reported to the Detroit and Los Angeles Surveillance, Epidemiology, and End Results registries were identified and surveyed shortly after receipt of surgical treatment (response rate, 77.4%; n = 1,844).
Mean age was 60.1 years; 70.2% of the women were white, 18.0% were African American, and 11.8% were from other ethnic groups. Overall, 30.2% of women received mastectomy as initial treatment. Most women reported that they made the surgical decision (41.0%) or that the decision was shared (37.1%); 21.9% of patients reported that their surgeon made the decision with or without their input. Among white women, only 5.3% of patients whose surgeon made the decision received mastectomy compared with 16.8% of women who shared the decision and 27.0% of women who made the decision (P < .001, adjusted for clinical factors, predisposing factors, and number of surgeons visited). However, this association was not observed for African American women (Wald test 10.0, P = .041).
Most women reported that they made or shared the decision about surgical treatment. More patient involvement in decision making was associated with greater use of mastectomy. Racial differences in the association of involvement with receipt of treatment suggest that the decision-making process varies by racial groups.
In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995.
Information was available on 42,000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23,500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (<10%, 17,000 women; >10%, 25,000 women).
About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. Among the 25,000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44.6% versus 49.5% (absolute reduction 5.0%, SE 0.8, 2p<0.00001). These 25,000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1% (reduction 5.4%, SE 1.3, 2p=0.0002; overall mortality reduction 4.4%, SE 1.2, 2p=0.0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004).
In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.
We report on acute toxicities as well as the early cosmetic outcome of patients receiving intraoperative radiotherapy (IORT) followed by whole-breast radiotherapy (WBRT) compared to patients treated with standard WBRT alone.
From 2/2002 until 2/2005, 84 breast cancer patients were treated with IORT during breast-conserving surgery (BCS) as a boost (20 Gy/50 kV X-rays) followed by WBRT. After wound healing, all IORT patients were treated with WBRT at a total dose of 46 Gy. For the purpose of comparison, 53 patients treated consecutively between 1/2003 and 12/2004 in our institution with BCS followed by WBRT at a total dose of 50-66 Gy, were analyzed. All patients had a defined followup schedule. Toxicities were prospectively documented using the CTC/EORTC Score. Cosmesis was evaluated after 6 months using a 1-4 score.
Treatment was well tolerated with no grade 3/4 acute toxicity. Rare adverse effects following IORT included wound healing problems (2%), erythema grade I-II (3%), palpable seroma (6%) and mastitis (2-4%). The number of patients with induration of the tumor bed was comparably low.
IORT with the IntrabeamTM system applied as a boost during BCS, followed by 46 Gy WBRT, exerts similar acute toxicity as standard WBRT. Further follow-up is needed to assess long-term toxicity and efficacy.
Postoperative radiotherapy, which forms part of breast-conserving therapy, may not need to encompass the whole breast. Apart from the consumption of huge resources and patients' time, postoperative radiotherapy deters many women from receiving the benefits of breast-conserving surgery, forcing them to choose a mastectomy instead. If radiotherapy could be given in the operating theatre immediately after surgery, many of these disadvantages could be overcome. One striking fact about local recurrence after breast-conserving surgery is that most occurs in the area of breast immediately next to the primary tumour; this is despite the finding that two-thirds of mastectomy samples have microscopic tumours distributed throughout the breast, even when radiotherapy is omitted. Thus, only the area adjacent to the tumour may need treatment with radiotherapy. On the basis of this premise, clinical scientists have used new technology to administer radiotherapy to the area at greatest risk of local recurrence, with the aim of completing the whole local treatment in one sitting. In this review, we have elaborated on the rationale and different methods of delivery of intraoperative radiotherapy. If this approach is validated by the results of current randomised trials, it could save time, money, and breasts.