Acute and Long-Term Toxicity after Planned Intraoperative Boost and Whole Breast Irradiation in High-Risk Patients with Breast Cancer-Results from the Targeted Intraoperative Radiotherapy Boost Quality Registry (TARGIT BQR).

In the context of breast cancer treatment optimization, this study prospectively examines the feasibility and outcomes of utilizing intraoperative radiotherapy (IORT) as a boost in combination with standard external beam radiotherapy (EBRT) for high-risk patients. Different guidelines recommend such a tumor bed boost in addition to whole breast irradiation with EBRT for patients with risk factors for local breast cancer recurrence. The TARGIT BQR (NCT01440010) is a prospective, multicenter registry study aimed at ensuring the quality of clinical outcomes. It provides, for the first time, data from a large cohort with a detailed assessment of acute and long-term toxicity following an IORT boost using low-energy X-rays. Inclusion criteria encompassed tumors up to 3.5 cm in size and preoperative indications for a boost. The IORT boost, administered immediately after tumor resection, delivered a single dose of 20 Gy. EBRT and systemic therapy adhered to local tumor board recommendations. Follow-up for toxicity assessment (LENT SOMA criteria: fibrosis, teleangiectasia, retraction, pain, breast edema, lymphedema, hyperpigmentation, ulceration) took place before surgery, 6 weeks to 90 days after EBRT, 6 months after IORT, and then annually using standardized case report forms (CRFs). Between 2011 and 2020, 1133 patients from 10 centers were preoperatively enrolled. The planned IORT boost was conducted in 90%, and EBRT in 97% of cases. Median follow-up was 32 months (range 1-120, 20.4% dropped out), with a median age of 61 years (range 30-90). No acute grade 3 or 4 toxicities were observed. Acute side effects included erythema grade 1 or 2 in 4.4%, palpable seroma in 9.1%, punctured seroma in 0.3%, and wound healing disorders in 2.1%. Overall, chronic teleangiectasia of any grade occurred in 16.2%, fibrosis grade ≥ 2 in 14.3%, pain grade ≥ 2 in 3.4%, and hyperpigmentation in 1.1%. In conclusion, a tumor bed boost through IORT using low-energy X-rays is a swift and feasible method that demonstrates low rates in terms of acute or long-term toxicity profiles in combination with whole breast irradiation.

Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A.

The randomized phase III trial TARGIT A showed non-inferiority regarding local control after intraoperative radiotherapy (IORT 20 Gy which was followed by whole breast radiotherapy (WBRT) in patients with risk factors only) in comparison to standard WBRT (50-56 Gy) after breast-conserving surgery in selected patients. This is the first analysis of long-term toxicities in the setting of TARGIT. Between 02/2002 and 12/2008, 305 patients were treated within TARGIT A (Arm A: n = 34 IORT, n = 20 IORT + WBRT for risk factors; Arm B WBRT: n = 55) or received IORT as a planned boost (control group: n = 196) at a single center. Toxicity was assessed according to the LENT SOMA scales. No significant differences were seen between Arm A and Arm B regarding fibrosis, breast edema, retraction, ulceration, lymphedema, hyperpigmentation, and pain. Arm A had significantly less telangiectases compared to Arm B (p = 0.049). In the subanalysis (Arm A IORT vs. Arm A IORT + WBRT vs. Arm B), fibrosis had a cumulative rate of 5.9 versus 37.5 versus 18.4 %, respectively (38.2 % IORT boost control group), at 3 years. No telangiectases were seen after IORT alone (0 % Arm A IORT vs. 17.5 % Arm A IORT + WBRT vs. 17.7 % Arm B). The hazard ratio of higher grade toxicity as first event was 0.46 (95 % CI, 0.26-0.83) for Arm A IORT as compared to Arm B (p = 0.010). No recurrences were seen after a median follow-up of 40 months (Arm A) and 42 months (Arm B). With its very low chronic skin toxicity rates and outstanding long-term results regarding toxicity and local control, IORT with 50 kV X-rays is a safe and effective method for treatment of selected breast cancer patients.

Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: 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).

Single-center long-term follow-up after intraoperative radiotherapy as a boost during breast-conserving surgery using low-kilovoltage x-rays.

BACKGROUND: Intraoperative radiotherapy (IORT) during breast-conserving surgery as a boost followed by whole-breast radiotherapy is increasingly used. METHODS: Between February 2002 and December 2008, a total of 197 patients were treated with IORT as a boost (20 Gy, 50 kV x-rays; Intrabeam System, Carl Zeiss Surgical, Oberkochen, Germany) during breast-conserving surgery, followed by whole-breast radiotherapy (46-50 Gy). Systemic therapy was provided according to the St. Gallen consensus. Patients were recalled every 6-12 months for follow-up. Findings were scored according to the LENT-SOMA scale. RESULTS: Median age was 61.8 (range 30-84) years, and median follow-up was 37 (range 5-91) months. There were T1, T2, and Tx tumors in 129, 67, and 1 patients, respectively, and N0, N1, N2, and N3 disease in 144, 36, 15, and 2 patients, respectively. Until December 2009, 5 local invasive relapses, 1 local ductal carcinoma-in-situ, 1 axillary relapse, 6 secondary cancers, and 11 distant metastases were seen, resulting in a 5-year disease-free survival of 81.0% and an overall survival of 91.3%. Local relapse-free survival (invasive cancers) at 3 and 5 years was 97.0%. After a follow-up of 5 years (n =58), only 8 patients (13.8%) had chronic skin toxicities, and 2 patients (3.4%) had a marked increase in density (fibrosis III), while 62.0% had no/barely palpable fibrosis 0-I. Other toxicities observed included severe pain (n = 4, 6.9%), retraction (n =17, 29.3%), edema of the breast (n =1, 1.7%), and lymphedema in general (n =2, 3.4%). CONCLUSIONS: After IORT as a tumor bed boost with low-kilovoltage x-rays followed by whole-breast radiotherapy, low local recurrence and chronic toxicity rates were seen after 5-year follow-up.

Health-related quality of life after breast-conserving surgery and intraoperative radiotherapy for breast cancer using low-kilovoltage X-rays.

BACKGROUND: Intraoperative radiotherapy (IORT) is currently being evaluated as a novel approach during breast-conserving surgery (BCS). IORT can be used either as a tumor bed boost followed by external-beam radiotherapy (EBRT) or as a single treatment. In a matched-pair study, we assessed quality of life (QoL) in 69 patients with early breast cancer treated with BCS and/or IORT and/or EBRT. METHODS: Patients were matched for age and time since BCS. IORT was provided with 50 kV x-rays (Intrabeam) delivering 20 Gy at the applicator surface. EBRT (46 to 50 Gy in 2-Gy fractions in the IORT with EBRT group, and 56 Gy in 2-Gy fractions in the EBRT group) was initiated after completion of wound healing and/or chemotherapy. The mailed questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 and BR23, FACT-F, HADS, Body Image Scale, and Rosenberg Self-Esteem Scale. At 18 to 70 months' follow-up (median 47 months), all patients were disease free. RESULTS: We found only a few differences between the three groups. There was a trend toward more pain (mean ± standard deviation; 42.8 ± 32.9 vs. 27.5 ± 34.7) and reduced QoL (57.6 ± 20.7 vs. 70.3 ± 23.9) after IORT with EBRT compared with EBRT, respectively. IORT patients reported comparable QoL (70.3 ± 23.0), and less breast symptoms and body image concerns compared to EBRT (8.6 ± 12.3 vs. 19.2 ± 23.8, and 1.7 ± 3.3 vs. 3.4 ± 4.4, respectively). IORT alone resulted in significantly fewer breast symptoms (8.6 ± 12.3; P = 0.012) and less pain (23.9 ± 24.5, P = 0.041) compared with IORT with EBRT (26.1 ± 27.6; 42.8 ± 32.9, respectively). CONCLUSIONS: Patients with early breast cancer after BCS and IORT with or without EBRT present with comparable QoL like patients receiving EBRT without a boost. IORT patients show the lowest rate of breast symptoms.

[Is cardiotoxicity still an issue after breast-conserving surgery and could it be reduced by multifield IMRT?]. / Ist die Kardiotoxizität der Radiotherapie im Rahmen des Brusterhalts überhaupt noch relevant, und könnte sie durch Mehrfelder-IMRT gesenkt werden?

BACKGROUND: Postoperative radiotherapy after breast cancer surgery effectively reduces local relapses. A survival benefit after breast conservation, however, has only been proven recently which was in part due to excessive cardiac mortality of patients who had been treated with radiotherapy in the past. MATERIAL AND METHODS: The literature on postoperative radiotherapy for breast cancer was reviewed with regard to cardiac toxicity as the basis for hypothesis generation. RESULTS: From numerous publications on cardiac toxicity of breast cancer radiotherapy, the following pattern emerges: in series where a high radiation dose was applied to a significant percentage of the heart (postmastectomy and postlumpectomy series) cardiac toxicity/mortality was increased versus a nonexposed cohort or for left over right disease. If, however, a relevant exposure of cardiac muscle could be more or less excluded based on the technique used (mainly more recent postlumpectomy radiotherapy), no cardiac toxicity was observed. Series for which individual dose exposure varied or could not be clarified also came to varying conclusions. Also due to retrospectively unclear dose distributions, an exact quantification of tolerance doses/effects of different geographic dose distribution patterns could not be performed to date. A particularly difficult question to answer is the threshold volume for clinically relevant cardiotoxicity with tangential radiotherapy at prescription doses. As a consequence, this precludes an estimate in which situations multifield intensity-modulated radiotherapy (IMRT) with its characteristic dose distribution pattern of a larger volume exposed to intermediate doses and higher mean/median heart doses (as shown in Figure 1) might be preferable. CONCLUSION: This review updates the database on cardiac toxicity of breast cancer radiotherapy with special emphasis regarding the issues related to the clinical use of IMRT. Multifield IMRT may reduce the cardiac risk for a small subset of patients at excessive risk with conventional tangential radiotherapy due to unfavorable thoracic geometry, for whom partial-breast radiotherapy is not an option. Due to further concern about the effects of intermediate doses to larger heart volumes, potentially increased contralateral cancer risk and the long latency of clinically apparent toxicity, the introduction of breast IMRT should be closely followed. Accompanying functional studies may have the potential to detect cardiac toxicity at an earlier time.

Intraoperative radiotherapy (IORT) is an option for patients with localized breast recurrences after previous external-beam radiotherapy.

BACKGROUND: For patients suffering of recurrent breast cancer within the irradiated breast, generally mastectomy is recommended. The normal tissue tolerance does not permit a second full-dose course of radiotherapy to the entire breast after a second breast-conserving surgery (BCS). A novel option is to treat these patients with partial breast irradiation (PBI). This approach is based on the hypothesis that re-irradiation of a limited volume will be effective and result in an acceptable frequency of side effects. The following report presents a single center experience with intraoperative radiotherapy (IORT) during excision of recurrent breast cancer in the previously irradiated breast. METHODS: Between 4/02 and 11/06, 15 patients were treated for in-breast recurrences at a median of 10 years (3-25) after previous EBRT (10 recurrences in the initial tumor bed, 3 elsewhere in-breast failures, 2 invasive recurrences after previous DCIS). Additional 2 patients were selected for IORT with new primary breast cancer after previous partial breast EBRT for treatment of Hodgkin's disease. IORT with a single dose of 14.7 - 20 Gy 50 kV X-rays at the applicator surface was delivered with the Intrabeam-device (Carl Zeiss, Oberkochen, Germany). RESULTS: After a median follow-up of 26 months (1-60), no local recurrence occurred. 14 out of 17 patients are alive and free of disease progression. Two patients are alive with distant metastases. One patient died 26 months after BCS/IORT due to pulmonary metastases diagnosed 19 months after BCS/IORT. Acute toxicity after IORT was mild with no Grade 3/4 toxicities and cosmetic outcome showed excellent/good/fair results in 7/7/3 cases. CONCLUSION: IORT for recurrent breast cancer using low energy X-rays is a valuable option for patients with recurrent breast cancer after previous radiotherapy.

Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer.

PURPOSE: To establish the feasibility and efficacy of capecitabine in combination with weekly irinotecan (CAPIRI) with concurrent pelvic radiotherapy (RT) in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Nineteen patients with rectal cancer clinical stage T3-4, Nx received weekly irinotecan 50 mg/m(2) (days 1, 8, 15, 22, 29) and two doses of capecitabine (days 1 through 38; dose level [DL] I, 500 mg/m(2) bid; DL II, 625 mg/m(2) bid) according to phase I methodology. Three-dimensional conformal RT was given to a dose of 50.4 Gy (45 Gy + 5.4 Gy). RESULTS: On DL I, no dose-limiting toxicities occurred, whereas diarrhea grade 3 affected three of seven patients on DL II. Twelve patients were treated on DL I and received a median relative dose-intensity of 100% for both drugs. Grade 3 or 4 adverse events were observed in only one of these patients (asthenia grade 3). All patients underwent surgery and R0 resection was achieved in all patients. Pathologic complete remission was observed in four patients and another five patients had only microfoci of residual tumor. CONCLUSION: Preoperative chemoradiotherapy with CAPIRI is feasible and well tolerated. The preliminary efficacy is good, and the tolerability is at least comparable with data for fluorouracil plus irinotecan chemoradiotherapy. Larger phase II trials of the CAPIRI-RT schedule clearly are warranted.

Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery.

PURPOSE: Intraoperative radiotherapy (IORT) as a boost for breast cancer delivers a high single dose of radiation to a late-reacting tissue; therefore late toxicity is of particular interest, and long-term follow-up is warranted. To date there are only limited data available on breast cancer patients treated with IORT using low energy X-rays. We analyzed toxicity and cosmesis after IORT as a boost with a minimum follow-up of 18 months. METHODS AND MATERIALS: A total of 73 patients treated with IORT (20 Gy/50 kV X-rays; INTRABEAM [Carl Zeiss Surgical, Oberkochen, Germany]) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT, 46 Gy) underwent a prospective, predefined follow-up (median, 25 months; range 18-44 months), including clinical examination and breast ultrasound at 6-months and mammographies at 1-year intervals. Toxicities were documented using the common toxicity criteria (CTC)/European Organization for Research and Treatment of Cancer and the LENT-SOMA score. Cosmesis was evaluated with a score from 1 to 4. RESULTS: The IORT in combination with WBRT was well tolerated, with no Grade 3 or 4 skin toxicities and no telangiectasias. Fibrosis of the entire breast was observed in 5% of the patients. A circumscribed fibrosis around the tumor bed was palpable in up to 27% with a peak around 18 months after therapy and a decline thereafter. The observed toxicitiy rates were not influenced by age, tumor stage, or systemic therapy. The cosmetic outcome was good to excellent in>or=90% of cases. CONCLUSIONS: After IORT of the breast using low-energy X-rays, no unexpected toxicity rates were observed during long-term-follow-up.

Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer.

PURPOSE: To establish the feasibility and efficacy of chemotherapy with capecitabine, weekly irinotecan, cetuximab, and pelvic radiotherapy for patients with locally advanced rectal cancer. METHODS AND MATERIALS: Twenty patients with rectal cancer (clinical Stage uT3-T4 or N+) received a standard dosing regimen of cetuximab (400 mg/m(2) on Day 1 and 250 mg/m(2) on Days 8, 15, 22, and 29) and escalating doses of irinotecan and capecitabine according to phase I methods: dose level I, irinotecan 40 mg/m(2) on Days 1, 8, 15, 22, and 29 and capecitabine 800 mg/m(2) on Days 1-38; dose level II, irinotecan 40 mg/m(2) and capecitabine 1000 mg/m(2); and dose level III, irinotecan 50 mg/m(2) and capecitabine 1000 mg/m(2). Radiotherapy was given to a dose of 50.4 Gy (45 Gy plus 5.4 Gy). Resection was scheduled 4-5 weeks after termination of chemoradiotherapy. RESULTS: On dose level I, no dose-limiting toxicities occurred; however, Grade 3 diarrhea affected 1 of 6 patients on dose level II. Of 5 patients treated at dose level III, 2 exhibited dose-limiting toxicity (diarrhea in 2 and nausea/vomiting in 1). Therefore, dose level II was determined as the recommended dose for future studies. A total of 10 patients were treated on dose level II and received a mean relative dose intensity of 100% of cetuximab, 94% of irinotecan, and 95% of capecitabine. All patients underwent surgery. Five patients had a pathologically complete remission and six had microfoci of residual tumor only. CONCLUSION: Preoperative chemoradiotherapy with cetuximab, capecitabine, and weekly irinotecan is feasible and well tolerated. The preliminary efficacy is very promising. Larger phase II trials are ongoing.

Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost.

PURPOSE: Patients undergoing breast-conserving surgery were offered boost radiotherapy with targeted intraoperative radiotherapy (TARGIT) using the Intrabeam system to test the feasibility, safety, and efficacy of the new approach. METHODS AND MATERIALS: We treated 302 cancers in 301 unselected patients. This was not a low-risk group. One-third of patients (98/301) were younger than 51 years of age. More than half of the tumors (172, 57%) were between 1 cm and 2 cm, and one-fifth (62, 21%) were >2 cm; 29% (86) had a Grade 3 tumor and, in 29% (87), axillary lymph nodes contained metastasis. After primary surgery, 20 Gy was delivered intraoperatively to the surface of the tumor bed, followed by external-beam radiotherapy (EBRT), but excluding the usual boost. RESULTS: The treatment was well tolerated. The follow-up ranged from 3 to 80 months (164 and 90 patients completed 2 and 3 years follow-up, respectively). Four patients (1.3%) had local recurrence. The Kaplan-Meier estimate of local recurrence is 2.6% (SE = 1.7) at 5 years. This compares favorably with the 4.3% recurrence rate in boosted patients from the EORTC boost study, in which only 8.1% patients were node-positive, as opposed to 29% in our series. CONCLUSION: Targeted intraoperative radiotherapy combined with EBRT results in a low local recurrence rate. This could be attributed to both accurate targeting and timeliness of the treatment. These data support the need for a randomized trial to test whether the TARGIT boost is superior to conventional external boost, especially in high-risk women.

TARGeted Intraoperative radiotherapy (TARGIT): an innovative approach to partial-breast irradiation.

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.

Radiobiological aspects of intraoperative radiotherapy (IORT) with isotropic low-energy X rays for early-stage breast cancer.

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.

Intraoperative radiotherapy (IORT) for breast cancer using the Intrabeam system.

INTRODUCTION: Intraoperative radiotherapy (IORT) with low-energy X-rays (30-50 KV) is an innovative technique that can be used both for accelerated partial breast irradiation (APBI) and intraoperative boosting in patients affected by breast cancer. Immediately after tumor resection the tumor bed can be treated with low-distance X-rays by a single high dose. Whereas often a geographic miss in covering the boost target occurs with external beam boost radiotherapy (EBRT), the purpose of IORT is to cover the tumor bed safely. This report will focus on the feasibility and technical aspects of the Intrabeam device and will summarize our experience with side effects and local control. MATERIALS AND METHODS: Between February 2002 and June 2003 57 breast cancer patients, all eligible for breast conserving surgery (BCS), were treated at the Mannheim Medical Center with IORT using the mobile X-ray system Intrabeam. The patient population in this feasibility study was not homogeneous consisting of 49 patients with primary stage I or II breast cancer, seven with local recurrence after previous EBRT and one with a second primary in a previously irradiated breast. The selection criteria for referral for IORT included tumor size, tumor cavity size, margin status and absence of an extensive intraductal component. The previously irradiated patients with local recurrences and 16 others received IORT as single modality. In all other cases IORT was followed by EBRT with a total dose of 46 Gy in 2-Gy fractions. The intraoperatively delivered dose after tumor resection was 20 Gy prescribed to the applicator surface. EBRT was delivered with a standard two-tangential-field technique using linear accelerators with 6- or 18-MV photons. Patients were assessed every three months by their radiation oncologist or surgeon during the first year after treatment and every six months thereafter. Breast ultrasound for follow-up was done every six months and mammographies once yearly. Acute side effects were scored according to the CTC/EORTC score and late side effects according to the Lent-Soma classification. RESULTS: Twenty-four patients received IORT only; eight patients because they had received previous radiotherapy, 16 because of a very favorable risk profile or their own preference. Thirty-three patients with tumor sizes between 1 and 30 mm and no risk factors were treated by IORT as a boost followed by EBRT. The Intrabeam system was used for IORT. The Intrabeam source produces 30-50 KV X-rays and the prescribed dose is delivered in an isotropic dose distribution around spherical applicators. Treatment time ranged between 20 and 48 minutes. No severe acute side effects or complications were observed during the first postoperative days or after 12 months. One local recurrence occurred 10 months after surgery plus IORT followed by EBRT. In two patients distant metastases were diagnosed shortly after BCS. DISCUSSION: IORT with the Intrabeam system is a feasible method to deliver a single high radiation dose to breast cancer patients. As a preliminary boost it has the advantage of reducing the EBRT course by 1.5 weeks, and as APBI it might be a promising tool for patients with a low risk of recurrence. The treatment is well tolerated and does not cause greater damage than the expected late reaction in normal tissue.

Cardiac Function After Multimodal Breast Cancer Therapy Assessed With Functional Magnetic Resonance Imaging and Echocardiography Imaging.

PURPOSE: Breast intensity modulated radiation therapy (IMRT) reduces high-dose heart volumes but increases low-dose volumes. We prospectively assessed heart changes after 3D conformal RT (3DCRT) and IMRT for left-sided breast cancer. Heart dose was analyzed individually, 3DCRT patients were moderately exposed, and IMRT was performed only in patients with unacceptably high heart doses upon 3DCRT planning. METHODS AND MATERIALS: In 49 patients (38 patients received 3DCRT; 11 patients received IMRT; and 20 patients received neoadjuvant or adjuvant chemotherapy) magnetic resonance imaging (MRI) and echocardiography were performed before and at 6, 12, and 24 months after treatment. RESULTS: Mean heart dose for IMRT was 12.9 ± 3.9 Gy versus 4.5 ± 2.4 Gy for 3DCRT. Heart volumes receiving >40 Gy were 2.6% (3DCRT) versus 1.3% (IMRT); doses were >50 Gy only with 3DCRT. Temporary ejection fraction (EF) decrease was observed on MRI after 6 months (63%-59%, P=.005) resolving at 24 months. Only 3 patients had pronounced largely transient changes of EF and left ventricular enddiastolic diameter (LVEDD). Mitral (M) and tricuspid (T) annular plane systolic excursion (MAPSE and TAPSE) were reduced over the whole cohort (still within normal range). After 24 months left ventricular remodeling index decreased in patients receiving chemotherapy (0.80 vs 0.70, P=.028). Neither wall motion abnormalities nor late enhancements were found. On echocardiography, in addition to EF findings that were similar to those on MRI, global strain was unchanged over the whole cohort at 24 months after a transient decrease at 6 and 12 months. Longitudinal strain decreased in the whole cohort after 24 months in some segments, whereas it increased in others. CONCLUSIONS: Until 24 months after risk-adapted modern multimodal adjuvant therapy, only subclinical cardiac changes were observed in both 3DCRT patients with inclusion of small to moderate amounts of heart volume in RT tangents and in the patients treated with IMRT and reduced high-dose heart exposure.

Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: results from the randomized phase III trial TARGIT-A.

BACKGROUND: Intraoperative radiotherapy (IORT) is a new treatment approach for early stage breast cancer. This study reports on the effects of IORT on radiation-related quality of life (QoL) parameters. METHODS: Two hundred and thirty women with stage I-III breast cancer (age, 31 to 84 years) were entered into the study. A single-center subgroup of 87 women from the two arms of the randomized phase III trial TARGIT-A (TARGeted Intra-operative radioTherapy versus whole breast radiotherapy for breast cancer) was analyzed. Furthermore, results were compared to non-randomized control groups: n = 90 receiving IORT as a tumor bed boost followed by external beam whole breast radiotherapy (EBRT) outside of TARGIT-A (IORT-boost), and n = 53 treated with EBRT followed by an external-beam boost (EBRT-boost). QoL was collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 (QLQ-C30) and BR23 (QLQ-BR23). The mean follow-up period in the TARGIT-A groups was 32 versus 39 months in the non-randomized control groups. RESULTS: Patients receiving IORT alone reported less general pain (21.3 points), breast (7.0 points) and arm (15.1 points) symptoms, and better role functioning (78.7 points) as patients receiving EBRT (40.9; 19.0; 32.8; and 60.5 points, respectively, P < 0.01). Patients receiving IORT alone also had fewer breast symptoms than TARGIT-A patients receiving IORT followed by EBRT for high risk features on final pathology (IORT-EBRT; 7.0 versus 29.7 points, P < 0.01). There were no significant differences between TARGIT-A patients receiving IORT-EBRT compared to non-randomized IORT-boost or EBRT-boost patients and patients receiving EBRT without a boost. CONCLUSIONS: In the randomized setting, important radiation-related QoL parameters after IORT were superior to EBRT. Non-randomized comparisons showed equivalent parameters in the IORT-EBRT group and the control groups.

Factors of influence on acute skin toxicity of breast cancer patients treated with standard three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery (BCS).

PURPOSE/OBJECTIVES: Standard 3D-CRT after BCS may cause skin toxicity with a wide range of intensity including acute effects like erythema or late effects. In order to reduce these side effects it is mandatory to identify potential factors of influence in breast cancer patients undergoing standard three-dimensional conformal radiation therapy (3D-CRT) of the breast and modern systemic therapy. MATERIALS/METHODS: Between 2006 and 2010 a total of 211 breast cancer patients (median age 52,4 years, range 24-77) after BCS consecutively treated in our institution with 3D-CRT (50 Gy whole breast photon radiotherapy followed by 16 Gy electron boost to the tumorbed) were evaluated with special focus on documented skin toxicity at the end of the 50 Gy-course. Standardized photodocumentation of the treated breast was done in each patient lying on the linac table with arms elevated. Skin toxicity was documented according to the common toxicity criteria (CTC)-score. Potential influencing factors were classified in three groups: patient-specific (smoking, age, breast size, body mass index = BMI, allergies), tumor-specific (tumorsize) and treatment-specific factors (antihormonal therapy with tamoxifen or aromatase inhibitors, chemotherapy). Uni- and multivariate statistical analyses were done using IBM SPSS version 19. RESULTS: After 50 Gy 3D-CRT to the whole breast 28.9% of all 211 patients had no erythema, 62.2% showed erythema grade 1 (G1) and 8.5% erythema grade 2. None of the patients had grade 3/4 (G3/4) erythema.In univariate analyses a significant influence or trend on the development of acute skin toxicities (erythema G0 versus G1 versus G2) was observed for larger breast volumes (p=0,004), smoking during radiation therapy (p=0,064) and absence of allergies (p=0,014) as well as larger tumorsize (p=0,009) and antihormonal therapy (p=0.005).Neither patient age, BMI nor choice of chemotherapy showed any significant effect on higher grade toxicity. In the multivariate analysis, factors associated with higher grade skin toxicity were larger breast target volume (p=0,003), smoking (p=0,034) and absence of allergies (p=0,002). CONCLUSION: Patients treated in this study showed less objectively documented skin toxicity after 50 Gy 3D-CRT compared to similar patient cohorts. Factors associated with higher grade skin toxicity were smoking during 3D-CRT, absence of allergies and larger breast volumes.

Intraoperative radiotherapy during breast-conserving surgery using a miniature x-ray generator (Intrabeam®): theoretical and experimental background and clinical experience.

Breast cancer is currently the most frequent indication for intraoperative radiotherapy with increasing numbers worldwide. Intraoperative radiotherapy can be used as a tumor bed boost followed by whole breast radiotherapy, or as a distinct form of accelerated partial breast irradiation in selected patients. This article summarizes the theoretical background including pattern of recurrence and distribution of tumor cell foci in the breast and discusses the rationale for intraoperative radiotherapy, especially using a miniature x-ray generator (Intrabeam(®)). The concepts of how to avoid geographic and temporal miss by giving radiotherapy during surgery to the open wound cavity are described. Experimental and clinical experience is presented based on in vitro experiments and more than 300 treated patients in a single department with mature follow-up.

First description of MR mammographic findings in the tumor bed after intraoperative radiotherapy (IORT) of breast cancer.

The aim was to investigate changes in the tumor bed on magnetic resonance mammography (MRM) after intraoperative radiotherapy (IORT) and whether they would limit the diagnostic value of posttherapeutic MRM. We retrospectively investigated 36 patients undergoing MRM after IORT (median interval 2.8 years, range 0.4-7.1). Wound cavities with fat necrosis were common after IORT (81%). They were associated with persisting contrast enhancement, i.e., enhancement was mostly seen irrespective of the posttherapeutic interval. It normally presented as rim enhancement and did not cause any diagnostic uncertainty if viewed together with other tissue characteristics. We do not expect a limited diagnostic value of MRM after IORT.

Long-term results of targeted intraoperative radiotherapy (Targit) boost during breast-conserving surgery.

PURPOSE: We have previously shown that delivering targeted radiotherapy to the tumour bed intraoperatively is feasible and desirable. In this study, we report on the feasibility, safety, and long-term efficacy of TARGeted Intraoperative radioTherapy (Targit), using the Intrabeam system. METHODS AND MATERIALS: A total of 300 cancers in 299 unselected patients underwent breast-conserving surgery and Targit as a boost to the tumor bed. After lumpectomy, a single dose of 20 Gy was delivered intraoperatively. Postoperative external beam whole-breast radiotherapy excluded the usual boost. We also performed a novel individualized case control (ICC) analysis that computed the expected recurrences for the cohort by estimating the risk of recurrence for each patient using their characteristics and follow-up period. RESULTS: The treatment was well tolerated. The median follow up was 60.5 months (range, 10-122 months). Eight patients have had ipsilateral recurrence: 5-year Kaplan Meier estimate for ipsilateral recurrence is 1.73% (SE 0.77), which compares well with that seen in the boosted patients in the European Organization for Research and Treatment of Cancer study (4.3%) and the UK STAndardisation of breast RadioTherapy study (2.8%). In a novel ICC analysis of 242 of the patients, we estimated that there should be 11.4 recurrences; in this group, only 6 recurrences were observed. CONCLUSIONS: Lumpectomy and Targit boost combined with external beam radiotherapy results in a low local recurrence rate in a standard risk patient population. Accurate localization and the immediacy of the treatment that has a favorable effect on tumour microenvironment may contribute to this effect. These long-term data establish the long-term safety and efficacy of the Targit technique and generate the hypothesis that Targit boost might be superior to an external beam boost in its efficacy and justifies a randomized trial.