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.     

Intraoperative radiotherapy (IORT) as a boost in patients with early-stage breast cancer -- acute toxicity

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Intraoperative radiotherapy (IORT) for unresectable stage IVb pancreatic cancer

We evaluated the efficacy of IORT for unresectable Stage IVb (Japan Pancreas Society classification) pancreatic cancer. Twelve patients were treated with IORT, 17 with external beam radiotherapy (ERT) and 17 with chemotherapy (CHT, 8 patients doxorubicin-based, 7 patients 5-FU-based). Survival, hospital-free survival and pain relief were compared among the three groups. In the IORT group, 7 patients underwent bypass surgery, 3 celiac plexus blockade, 3 ERT, 2 hyperthermia and 2 CHT. In the ERT group, 1 patient underwent bypass surgery, 7 hyperthermia and 14 CHT. Distant metastases were more frequently found in the CHT group than in the IORT group. Median survival and median hospital-free survival were 208 and 79 days in the IORT group, 125 and 32 days in the ERT group and 76 and 9 days in the CHT group, respectively. Pain relief was obtained in 45% (5/11) of symptomatic patients after IORT and in 27% (4/15) after ERT. No patient (0/13) in the CHT group experienced pain relief. In conclusion, our experience suggests that IORT can reduce pain and improve QOL in patients with unresectable pancreatic cancer.     

Concepts and techniques of intraoperative radiotherapy (IORT) for breast cancer

The standard treatment for early breast cancer comprises wide local excision, sentinel lymph node biopsy or axillary lymph node dissection, adjuvant medical treatment and radiotherapy to the whole breast. Many studies suggest that local control plays a crucial role in overall survival. The local recurrence rate is estimated to be 1% per year and varies between 4 and 7% after 5 years and up to 10 to 20% in the long-term follow up. On the basis of low local recurrence rates the concept of whole breast irradiation comes up for discussion, and partial breast irradiation (PBI) is increasingly under consideration. Intraoperative radiotherapy (IORT) is referred to as the delivery of a single high dose of irradiation directly to the tumor bed (confined target) during surgery. PBI (limited field radiation therapy, accelerated partial breast irradiation APBI) is the irradiation exclusively confined to a breast volume, the tumor surrounding tissue (tumor bed) either during surgery or after surgery without whole breast irradiation. Various methods and techniques for IORT or PBI are under investigation. The advantage of a very short radiation time or the integration of the complete radiation treatment into the surgical procedure convinces at a first glance. The promising short-term results of those studies must not fail to mention that local recurrence rates could probably increase and furthermore give rise to distant metastases and a reduction in overall survival. The combination of IORT in boost modality and whole breast irradiation has the ability to reduce local recurrence rates. The EBCTCG overview approves that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality. This article is based on an invited lecture delivered at the 15th Annual Meeting of the Japanese Breast Cancer Society, held in Yokohama June 29-30, 2007.     

Intraoperative radiotherapy (IORT) for surgically resected brain metastases: outcome analysis of an international cooperative study

Journal of Neuro-Oncology - The ideal delivery of radiation to the surgical cavity of brain metastases (BMs) remains the subject of debate. Risks of local failure (LF) and radiation necrosis (RN)...     

Concepts and techniques of intraoperative radiotherapy (IORT) for breast cancer.

The standard treatment for early breast cancer comprises wide local excision, sentinel lymph node biopsy or axillary lymph node dissection, adjuvant medical treatment and radiotherapy to the whole breast. Many studies suggest that local control plays a crucial role in overall survival. The local recurrence rate is estimated to be 1% per year and varies between 4 and 7% after 5 years and up to 10 to 20% in the long-term follow up. On the basis of low local recurrence rates the concept of whole breast irradiation comes up for discussion, and partial breast irradiation (PBI) is increasingly under consideration. Intraoperative radiotherapy (IORT) is referred to as the delivery of a single high dose of irradiation directly to the tumor bed (confined target) during surgery. PBI (limited field radiation therapy, accelerated partial breast irradiation APBI) is the irradiation exclusively confined to a breast volume, the tumor surrounding tissue (tumor bed) either during surgery or after surgery without whole breast irradiation. Various methods and techniques for IORT or PBI are under investigation. The advantage of a very short radiation time or the integration of the complete radiation treatment into the surgical procedure convinces at a first glance. The promising short-term results of those studies must not fail to mention that local recurrence rates could probably increase and furthermore give rise to distant metastases and a reduction in overall survival. The combination of IORT in boost modality and whole breast irradiation has the ability to reduce local recurrence rates. The EBCTCG overview approves that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.     

Influence of obesity on biochemical and clinical failure after external-beam radiotherapy for localized prostate cancer

BACKGROUND: Several reports have shown that obesity is associated with increased risk of biochemical failure after radical prostatectomy. However, limited information is available regarding the impact of obesity on prostate cancer progression after radiotherapy. The current study sought to determine whether obesity was an independent predictor of biochemical failure (BF) and clinical recurrence (CF) among patients treated with external-beam radiotherapy (EBRT). METHODS: A retrospective analysis was performed on 873 patients receiving EBRT as the sole treatment for localized prostate cancer between 1988 and 2001. The Kaplan-Meier method, log-rank test, and Cox proportional hazards analyses were performed. RESULTS: Of the 873 patients, 18% were mildly obese and 5% were moderately to severely obese. Obesity was related to younger age at diagnosis (P < .001), more recent year of diagnosis (P = .03), and race (P = .03), with African-American men having the highest obesity rates. During a mean follow-up of 96 months, 295 patients experienced BF and 127 had CF. On multivariate analysis, controlling for clinical and treatment characteristics, increased body mass index (BMI) significantly predicted BF (hazards ratio [HR] = 1.04; 95% confidence interval [95% CI], 1.02-1.07) with a positive trend by BMI category (P = .001). Similar results were found when the outcome was CF; BMI remained an independent predictor of progression (HR = 1.05; 95% CI, 1.01-1.09), with a statistically significant trend by increased BMI category (P = .03). CONCLUSIONS: The current findings validate the important role of obesity, not only on BF but also on CF, and suggest a link to the biologic basis of tumor progression that can be therapeutically exploited.     

Intraoperative radiation therapy (IORT) for locally unresectable pancreatic cancer

To evaluate the therapeutic effect of IORT for unresectable locally advanced pancreatic cancer, 11 patients treated with IORT and 15 patients treated with palliative therapy only were retrospectively examined. The mean age of the IORT group was 61.9 years, 5 cases were classified into surgical stage IVa, and 6 into stage IVb. The mean age of the palliative therapy group was 69.1 years; 5 cases were classified into surgical stage IVa and 10 into stage IVb. The tumor size was measured in 6 cases in the IORT group, before and after IORT. The tumor was enlarged in 1 case, not changed in 4 cases, and reduced in 1 case. The serum CA19-9 level was measured in 8 cases of the IORT group. Serum CA19-9 was increased in 3 cases, not changed in 4 cases, and decreased in 1 case after IORT. ECOG pain scores were obtained in 9 patients who had complained of pain before IORT, and the score decreased in 7 cases. The median survival was 7.6 months in the IORT group and 3.0 months in the palliative therapy group. IORT may improve patients' QOL by decreasing their pain. However, further studies are necessary to confirm the efficacy of IORT for survival of locally unresectable pancreatic cancer patients, because the patient profile in this study was different in the two groups.     

Intraoperative radiation therapy (IORT) for previously untreated malignant gliomas

Background  

Intraoperative radiation therapy (IORT) is one of the methods used to deliver a large single dose to the tumor tissue while reducing the exposure of normal surrounding tissue. However, the usefulness of intraoperative electron therapy for malignant gliomas has not been established.     

TARGIT-E(lderly) - Prospective phase II study of intraoperative radiotherapy (IORT) in elderly patients with small breast cancer

ABSTRACT: BACKGROUND: Patients [greater than or equal to] 70 years with small, low-risk breast cancer who are operated but not irradiated show local relapse rates around 4% after 4 years. With adjuvant whole breast radiotherapy (WBRT) the local relapse rate drops to 1% after 4 years under Tamoxifen (5). It has been demonstrated (6, 12) that the efficacy of radiotherapy of the tumor bed only in a selected group can be non-inferior to WBRT. METHODS: This prospective, multicentric single arm phase II study is based on the protocol of the international TARGIT-A study. The TARGIT-E study should confirm the efficacy of a single dose of intraoperative radiotherapy (IORT) in a well selected group of elderly patients with small breast cancer and absence of risk factors. Patients will receive IORT (20 Gy with Intrabeam system/Carl Zeiss) during breast conserving surgery. In presence of risk factors postoperative WBRT will be added to complete the radiotherapeutic treatment according to international guidelines. Endpoints are the local relapse rate (within 2 cm of the tumor bed), ipsilateral in breast relapse, cancer-specific and overall survival and contralateral breast cancer as well as documentation of quality of life and cosmetic outcome. The expected local relapse rates are 0.5/1/1.5% after 2.5/5/7.5 years, respectively. Discontinuation of the trial is scheduled if rates of local relapse rates rise to 3/4/6% after 2.5/5/7.5 years. Power calculations result in 540 patients with a calculated dropout rate of 20% and loss to follow-up of 20%, an alpha of 0.01 and a beta 0.05. There will be a pre- and a post-pathology stratum (n=270 each). DISCUSSION: It is a pragmatic trial in which each participating centre has the option to modify entry criteria and criteria for WBRT according to this core protocol after consultation with the steering committee and local ethics committee (e.g. size, free margins). Only centers with access to the Intrabeam system (Carl Zeiss) can recruit patients into the trial. Its aim is to confirm the efficacy and toxicity of IORT in a well selected collective of elderly patients with breast cancer.     

Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer

BACKGROUND:

The long‐term survival of patients with high‐risk prostate cancer was compared after radical prostatectomy (RRP) and after external beam radiation therapy (EBRT) with or without adjuvant androgen‐deprivation therapy (ADT).

METHODS:

In total, 1238 patients underwent RRP, and 609 patients received with EBRT (344 received EBRT plus ADT, and 265 received EBRT alone) between 1988 and 2004 who had a pretreatment prostate‐specific antigen (PSA) level ≥ 20 ng/mL, a biopsy Gleason score between 8 and 10, or clinical tumor classification ≥ T3. The median follow‐up was 10.2 years, 6.0 years, and 7.2 years after RRP, EBRT plus ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer‐specific survival, and overall survival was evaluated using multivariate Cox proportional hazard regression analysis and a competing risk‐regression model.

RESULTS:

The 10‐year cancer‐specific survival rate was 92%, 92%, and 88% after RRP, EBRT plus ADT, and EBRT alone, respectively (P = .06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.51‐1.18; P = .23) or prostate cancer death (HR, 1.14; 95% CI, 0.68‐1.91; P = .61) were observed between patients who received EBRT plus ADT and patients who underwent RRP. The risk of all‐cause mortality, however, was greater after EBRT plus ADT than after RRP (HR, 1.60; 95% CI, 1.25‐2.05; P = .0002).

CONCLUSIONS:

RRP alone and EBRT plus ADT provided similar long‐term cancer control for patients with high‐risk prostate cancer. The authors concluded that continued investigation into the differing impact of treatments on quality‐of‐life and noncancer mortality will be necessary to determine the optimal management approach for these patients. Cancer 2011. © 2011 American Cancer Society.     

Intraoperative radiotherapy during breast conserving surgery in patients previously treated with radiotherapy for Hodgkin's disease

AIMS AND BACKGROUND: Women who have received radiotherapy for Hodgkin's disease have an increased risk of developing breast cancer. Breast-conserving surgery followed by breast irradiation is generally considered to be contraindicated in such patients owing to the high cumulative radiation dose to the breast. Mastectomy is therefore recommended as the preferred treatment option in these women. METHODS: We report 3 patients affected by breast cancer who had previously been treated with mantle radiation for Hodgkin's disease and on whom breast-conserving surgery and full-dose intraoperative radiotherapy with electrons (ELIOT) were performed. RESULTS: A total dose of 17 Gy (prescribed at 100% isodose) in one case and 21 Gy (at the 90% isodose) in two cases was delivered directly to the mammary gland without acute complications and with good cosmetic results. CONCLUSIONS: In women previously irradiated for Hodgkin's disease, ELIOT could avoid repeat irradiation of the whole breast, thereby permitting conservative surgical treatment.     

Breast conserving surgery in combination with intraoperative radiotherapy after previous external beam therapy: an option to avoid mastectomy

Purpose

Mastectomy is the standard procedure in patients with in-breast tumor recurrence (IBTR) or breast cancer after irradiation of the chest due to Hodgkin’s disease. In certain cases a second breast conserving surgery (BCS) in combination with intraoperative radiotherapy (IORT) is possible. To date, data concerning BCS in combination with IORT in pre-irradiated patients are limited. This is the first pooled analysis of this special indication with a mature follow-up of 5 years.

Methods

Patients with IBTR after external beam radiotherapy (EBRT; treated in two centers) for breast cancer were included. Patients with previous EBRT including the breast tissue due to other diseases were also included. IORT was performed with the Intrabeam?-device using low kV X-rays. Clinical data including outcome for all patients and toxicity for a representative cohort (LENT-SOMA scales) were obtained. Statistical analyses were done including Kaplan–Meier estimates for local recurrence, distant metastasis and overall survival.

Results

A total of 41 patients were identified (39 patients with IBTR, 2 with Hodgkin`s disease in previous medical history). Median follow-up was 58 months (range 4–170). No grade 3/4 acute toxicity occurred within 9 weeks. Local recurrence-free survival rate was 89.9% and overall survival was 82.7% at 5 years. Seven patients developed metastasis within the whole follow-up.

Conclusions

BCS in combination with IORT in IBTR in pre-irradiated patients is a feasible method to avoid mastectomy with a low risk of side effects and an excellent local control and good overall survival.

     

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.     

Intraoperative radiotherapy given as a boost after breast-conserving surgery in breast cancer patients

Conventional radiotherapy after breast-conserving therapy is confined to 50-55 Gy external beam radiation therapy (EBRT) to the whole breast and 10-16 Gy external boost radiation to the tumour bed or brachytherapy to the tumour bed. Local recurrence rate after breast-conserving surgery varies between 5 and 18%. External boost radiation can partially miss the tumour bed and therefore can result in local failure. Intra-operative radiotherapy (IORT) as a high precision boost can prevent a 'geographical miss'. From October 1998 to December 2000, 156 patients with stage I and stage II breast cancer were operated upon in a dedicated IORT facility. After local excision of the tumour, the tumour bed was temporarily approximated by sutures to bring the tissue in the radiation planning target volume. A single dose of 9 Gy was applied to the 90% reference isodose with energies ranging from 4 to 15 MeV, using round applicator tubes 4-8 cm in diameter. After wound healing, the patients received additional 51-56 Gy EBRT to the whole breast. No acute complications associated with IORT were observed. In 5 patients, a secondary mastectomy had to be performed because of tumour multicentricity in the final pathological report or excessive intraductal component. 2 patients developed rib necroses. In 7 patients, wound healing problems occurred. After a mean follow-up of 18 months, no local recurrences were observed. Cosmesis of the breast was very good and comparable to patients without IORT. Preliminary data suggest that IORT given as a boost after breast-conserving surgery could be a reliable alternative to conventional postoperative fractionated boost radiation by accurate dose delivery and avoiding geographical misses, by enabling smaller treatment volumes and complete skin-sparing and by reducing postoperative radiation time by 7-14 days.     

A new option for early breast cancer patients previously irradiated for Hodgkin's disease: intraoperative radiotherapy with electrons (ELIOT)

Introduction  

Patients who have undergone mantle radiotherapy for Hodgkin's disease (HD) are at increased risk of developing breast cancer. In such patients, breast conserving surgery (BCS) followed by breast irradiation is generally considered contraindicated owing to the high cumulative radiation dose. Mastectomy is therefore recommended as the first option treatment in these women.