Intraoperative radiotherapy for breast cancer.

Intra-operative radiotherapy (IORT) as a treatment for breast cancer is a relatively new technique that is designed to be a replacement for whole breast external beam radiotherapy (EBRT) in selected women suitable for breast-conserving therapy. This article reviews twelve reasons for the use of the technique, with a particular emphasis on targeted intra-operative radiotherapy (TARGIT) which uses X-rays generated from a portable device within the operating theatre immediately after the breast tumour (and surrounding margin of healthy tissue) has been removed. The delivery of a single fraction of radiotherapy directly to the tumour bed at the time of surgery, with the capability of adding EBRT at a later date if required (risk-adaptive technique) is discussed in light of recent results from a large multinational randomised controlled trial comparing TARGIT with EBRT. The technique avoids irradiation of normal tissues such as skin, heart, lungs, ribs and spine, and has been shown to improve cosmetic outcome when compared with EBRT. Beneficial aspects to both institutional and societal economics are discussed, together with evidence demonstrating excellent patient satisfaction and quality of life. There is a discussion of the published evidence regarding the use of IORT twice in the same breast (for new primary cancers) and in patients who would never be considered for EBRT because of their special circumstances (such as the frail, the elderly, or those with collagen vascular disease). Finally, there is a discussion of the role of the TARGIT Academy in developing and sustaining high standards in the use of the technique.

Biological dosimetry for breast cancer radiotherapy: a comparison of external beam and intraoperative radiotherapy.

PURPOSE: External beam radiotherapy (EBRT) is the gold standard adjuvant treatment after breast conserving surgery although a recent phase 3 trial has shown the non-inferiority of intraoperative radiotherapy (IORT). Radiation exposure of the heart and cardiac vessels causes an increase in morbidity and mortality following EBRT for breast cancer. We have used γ-H2AX foci formation in peripheral blood lymphocytes as a surrogate marker of dose delivered to the heart and great vessels and have assessed the feasibility of using this technique for biological dosimetry. METHODS: 34 patients were recruited, having either EBRT or IORT as part of a randomised controlled trial (TARGIT). Blood samples were taken prior to and after first fraction of radiotherapy, and the γ-H2AX biomarker then quantified. RESULTS: Data were available for 31 patients. Following TARGIT-IORT there was an increase of 0.203 foci per cell (range -1.436 to 1.275) compared with 0.935 foci per cell (range -0.679 to 2.216) in the EBRT group; this difference was highly significant (p = 0.009). As TARGIT-IORT treatment is completed with a single fraction, whilst EBRT requires at least 15 fractions, the actual difference is estimated to be many times more. CONCLUSIONS: These data show a significantly greater change in γ-H2AX foci number per cell following one fraction of EBRT compared to TARGIT-IORT. This is the first study to demonstrate this effect using a biomarker and demonstrates a proof of concept methodology for similar applications.

Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: This phase II randomized, placebo-controlled study was conducted to evaluate efficacy and safety of radium-223 in patients with castration-resistant prostate cancer (CRPC) and painful bone metastases. Twelve- and 18-month survival results were reported previously. Here we report 24-month overall survival (OS) and safety data from the period 12 to 24 months after the first injection of study medication. METHODS: Patients with CRPC and bone pain were randomized 1:1 to receive 4 injections of radium-223 (50 kBq/kg [n = 33]) or placebo (n = 31) after external-beam radiotherapy; each injection was given every 4 weeks. Endpoints for this report were 24-month OS, long-term safety, and treatment-related adverse events (AEs) occurring in the 12- to 24-month period. RESULTS: After 24 months, 10 (30%) patients were alive in the radium-223 group compared with 4 patients (13%) in the placebo group. Patients who received at least 1 dose of study medication had a median OS of 65 weeks in the radium-223 group vs. 46 weeks in the placebo group (log-rank P = .056). The hazard ratio (HR) for OS, adjusted for baseline covariates, was 0.476 (95% confidence interval [CI], 0.258-0.877; Cox regression P = .017). The most frequent cause of death for both arms was disease progression. There were no reports of treatment-related AEs or long-term hematologic toxicity during the 12- to 24-month follow-up. CONCLUSION: Radium-223 had a highly favorable safety profile, with no evidence of second malignancies at 24-month follow-up. The significant improvement in OS observed in patients receiving radium-223 vs. placebo suggests that treatment of bone disease with radium-223 has survival benefits.

Pacemaker and radiotherapy in breast cancer: is targeted intraoperative radiotherapy the answer in this setting?

We present the case of an 83 year old woman with a cardiac pacemaker located close in distance to a subsequently diagnosed invasive ductal carcinoma of the left breast. Short range intraoperative radiotherapy was given following wide local excision and sentinel node biopsy. The challenges of using ionising radiation with pacemakers is also discussed.

In vivo dosimetry for single-fraction targeted intraoperative radiotherapy (TARGIT) for breast cancer.

PURPOSE: In vivo dosimetry provides an independent check of delivered dose and gives confidence in the introduction or consistency of radiotherapy techniques. Single-fraction intraoperative radiotherapy of the breast can be performed with the Intrabeam compact, mobile 50 kV x-ray source (Carl Zeiss Surgical, Oberkochen, Germany). Thermoluminescent dosimeters (TLDs) can be used to estimate skin doses during these treatments. METHODS AND MATERIALS: Measurements of skin doses were taken using TLDs for 72 patients over 3 years of clinical treatments. Phantom studies were also undertaken to assess the uncertainties resulting from changes in beam quality and backscatter conditions in vivo. RESULTS: The mean measured skin dose was 2.9 ± 1.6 Gy, with 11% of readings higher than the prescription dose of 6 Gy, but none of these patients showed increased complications. Uncertainties due to beam hardening and backscatter reduction were small compared with overall accuracy. CONCLUSIONS: TLDs are a useful and effective method to measure in vivo skin doses in intraoperative radiotherapy and are recommended for the initial validation or any modification to the delivery of this technique. They are also an effective tool to show consistent and safe delivery on a more frequent basis or to determine doses to other critical structures as required.

Intraoperative radiotherapy in the treatment of breast cancer: a review of the evidence.

The surgical treatment of early breast cancer has evolved from the removal of the entire breast and surrounding tissues (mastectomy) to the removal of the tumour together with a margin of healthy tissue (lumpectomy). Adjuvant radiotherapy, however, is still mainly given to the whole breast. Furthermore, external beam radiotherapy is often given several months after initial surgery and requires the patient to attend the radiotherapy centre daily for several weeks. A single fraction of radiotherapy given during surgery directly to the tumour bed (intraoperative radiotherapy) avoids these problems. The rationale and level-1 evidence for the safety and efficacy of the technique are reviewed.

IL15 can reverse the unresponsiveness of Wilms' tumor antigen-specific CTL in patients with prostate cancer.

PURPOSE: The Wilms' tumor antigen 1 (WT1) is overexpressed in several leukemias and solid tumors, but there is currently limited information regarding its role in prostate cancer. This study aimed to investigate WT1 expression in prostate cancer, and to determine the number and function of WT1-specific T cells in the peripheral blood of patients. EXPERIMENTAL DESIGN: Immunohistochemistry was used to assess WT1 expression in cancer tissues. Human leukocyte antigen A2 (HLA-A2) tetramers served to detect WT1-specific T cells, and peptide-specific stimulation was used to assess T-cell function in vitro. RESULTS: Immunohistochemistry of tissue arrays comprising 36 cancer and 8 normal prostate samples revealed nuclear WT1 staining in 39% of cancer samples, but not in normal prostate tissues. Tetramer analysis revealed a low frequency of WT1-specific T cells in 20 of 38 HLA-A2-positive patients. In vitro stimulation with WT1 peptide plus interleukin 2(IL2) and interleukin 7 (IL7) did not lead to an accumulation of WT1-specific T cells in any of the patient samples, although all patients were able to generate T-cell responses against Melan-A/MART1 control peptide. Stimulation with WT1 peptide in the presence of interleukin 15 (IL15), a cytokine that was shown to reverse tolerance of murine tumor-specific T cells, was able to restore the expansion and IFNgamma production of WT1-specific T cells in a subgroup of prostate cancer patients. CONCLUSION: The observation that IL15 can restore the function of WT1-specific T cells that were unresponsive to IL2 has implications for vaccination and immunotherapeutic strategies that aim to enhance WT1-specific T cell immunity in patients.

Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study.

BACKGROUND: The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra. METHODS: Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat. FINDINGS: Median relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression). INTERPRETATION: (223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers.