The novel technique of delivering targeted intraoperative radiotherapy (Targit) for early breast cancer.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Targeted intra-operative radiotherapy (Targit): An innovative method of treatment for early breast cancer

Introduction:We believe that conservative treatment of earlybreast cancer may not require radiotherapy that encompasses the whole breast.We present here the clinico-pathological basis for this view, as well as anovel therapeutic approach that allows intra-operative radiotherapy to besafely and accurately delivered to the target tissues in a standard operatingtheatre. The rationale:Whole-organ analysis of mastectomy specimensreveals that 80% of occult cancer foci are situated remotefrom the index quadrant. In contrast, over 90% of localrecurrences after breast conservative therapy occur nearthe originaltumour, even when radiotherapy is not given. Therefore, the remote occultcancer foci may be clinically irrelevant and radiotherapy to the indexquadrant alone might be sufficient. A novel technique:The Photon Radiosurgery System (PRS) is aningenious portable electron-beam driven device that can typically deliverintra-operative doses of 5–20 Gy, respectively, to 1 cm and 0.2 cmfrom the tumour bed over about 22 min. The pliable breast tissue – thetarget – wraps around the source, providing perfect conformalradiotherapy. Being soft X-rays, the dose attenuates rapidly(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 bedboost with targeted intra-operative radiotherapy.There have been no major complications and no patient has developed localrecurrence, although the median follow-up time is short, at 24 months. Conclusion:It is safe and feasible to deliver targetedintra-operative radiotherapy (Targit) for earlybreast cancer. We have begun a randomised trial – the first of its kind– comparingTargitwith conventional six-week course ofradiotherapy. If proven equivalent in terms of local recurrence and cosmesis,it could eliminate the need for the usual six-week course ofpost-operative radiotherapy.     

Partial breast irradiation versus whole breast radiotherapy for early-stage breast cancer: a decision analysis

PURPOSE: To compare the quality-adjusted life expectancy between women treated with partial breast irradiation (PBI) vs. whole breast radiotherapy (WBRT) for estrogen receptor-positive early-stage breast cancer. METHODS AND MATERIALS: We developed a Markov model to describe health states in the 15 years after radiotherapy for estrogen receptor-positive early-stage breast cancer. Breast cancer recurrences were separated into local recurrences and elsewhere failures. Ipsilateral breast tumor recurrence (IBTR) risk was extracted from the Oxford overview, and rates and utilities were adapted from the literature. We studied two cohorts of women (aged 40 and 55 years), both of whom received adjuvant tamoxifen. RESULTS: Assuming a no evidence of disease (NED)-PBI utility of 0.93, quality-adjusted life expectancy after PBI (and WBRT) was 12.61 (12.57) and 12.10 (12.06) years for 40-year-old and 55-year-old women, respectively. The NED-PBI utility thresholds for preferring PBI over WBRT were 0.923 and 0.921 for 40-year-old and 55-year-old women, respectively, both slightly greater than the NED-WBRT utility. Outcomes were sensitive to the utility of NED-PBI, the PBI hazard ratio for local recurrence, the baseline IBTR risk, and the percentage of IBTRs that were local. Overall the degree of superiority of PBI over WBRT was greater for 55-year-old women than for 40-year-old women. CONCLUSIONS: For most utility values of the NED-PBI health state, PBI was the preferred treatment modality. This result was highly sensitive to patient preferences and was also dependent on patient age, PBI efficacy, IBTR risk, and the fraction of IBTRs that were local.     

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.     

Acute toxicity of intraoperative radiotherapy and external beam-accelerated partial breast irradiation in elderly breast cancer patients

Background and purpose

We investigated the acute toxicity of accelerated partial breast irradiation using external beam (EB-APBI) or intraoperative radiotherapy (IORT) techniques in elderly breast cancer patients.

Materials and methods

Women ≥ 60 years with unifocal breast tumors of ≤ 30 mm were eligible for this prospective multi-center cohort study. IORT was applied with electrons following lumpectomy (23.3 Gy). EB-APBI was delivered using 3D-CRT or IMRT in 10 daily fractions of 3.85 Gy within 6 weeks after surgery. Acute toxicity was scored using the CTCAE v3.0 at 3 months after treatment. Patient-reported symptoms were analyzed using visual analogue scales (VAS) for pain and fatigue (scale 0–10), and single items from the EORTC QLQ-C30 and Breast Cancer questionnaires.

Results

In total, 267 (IORT) and 206 (EB-APBI) patients were available for toxicity analysis. More patients experienced ≥ grade 2 CTCAE acute toxicity in the IORT group (10.4% IORT and 4.9% EB-APBI; p = 0.03); grade 3 toxicity was low (3.3% IORT and 1.5% EB-APBI; ns); and no grade 4 toxicity occurred. EB-APBI patients experienced less fatigue direct postoperatively (EORTC p < 0.00, VAS p < 0.00). After 3 months only pain, according to the VAS scale, was significantly worse in the EB-APBI group (p < 0.00).

Conclusion

Acute toxicity after IORT and EB-APBI treatment is acceptable.

     

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.     

Dosimetric study to assess the feasibility of intraoperative radiotherapy with electrons (ELIOT) as partial breast irradiation for patients with cardiac implantable electronic device (CIED)

Purpose

To report in-vivo dosimetry in the infraclavicular region, a potential site of a cardiac implantable electronic device (CIED) and to evaluate the absorbed dose from intraoperative radiotherapy with electrons (ELIOT).

Methods

27 non-cardiopathic breast cancer (BC) patients without CIED received quadrantectomy and ELIOT as partial breast irradiation. Before delivering ELIOT, two catheters, each containing eight thermoluminescent dosimeters (TLDs), were positioned in the infraclavicular region. TLDs internal catheter was located deep in the tumor bed while the external catheter was placed on patient’s skin.

Results

Data were available for 24/27 patients. The absorbed doses were referred to the dose of 21 Gy. Values measured by the external catheter were low, although statistically significant higher doses were found close to the applicator (mean values 0.26–0.49 Gy). External TLD doses in proximity of the applicator were lower than those detected by their internal counterparts. Values measured by the internal catheter TLDs varied according to the distance from the applicator while no correlation with tumor site and beam energy was found. The distance from the applicator to deliver <?2 Gy to a CIED was 2 cm, while from 2.5 cm the dose measured in all the patients became negligible.

Conclusions

This dosimetric study provided data to support the clinical use of ELIOT in BC patients having CIEDs as long as the suggested minimum safe distance of 2.5 cm is taken from the RT field in case of ELIOT single dose of 21 Gy, in the energy range of 6–10 MeV.

     

Objective assessment of cosmetic outcome after targeted intraoperative radiotherapy in breast cancer: results from a randomised controlled trial

The international randomised targeted intraoperative radiotherapy (TARGIT) trial has demonstrated evidence of non-inferiority between the novel technique of TARGIT (intra-operative radiotherapy with Intrabeam^®) and conventional external beam radiotherapy (EBRT) in women with early breast cancer in terms of the primary outcome measure of risk of local relapse within the treated breast. Cosmesis is an increasingly important outcome of breast conserving treatment with both surgery and radiotherapy contributing to this. It was unknown if the single high dose of TARGIT may lead to damaging fibrosis and thus impair cosmesis further, so we objectively evaluated the aesthetic outcome of patients within the TARGIT randomised controlled trial. We have used an objective assessment tool for evaluation of cosmetic outcome. Frontal digital photographs were taken at baseline (before TARGIT or EBRT) and yearly thereafter for up to 5 years. The photographs were analysed by BCCT.core, a validated software which produces a composite score based on symmetry, colour and scar. 342 patients were assessed, median age at baseline 64 years (IQR 59–68). The scores were dichotomised into Excellent and Good (EG), and Fair and Poor (FP). There were statistically significant increases in the odds of having an outcome of EG for patients in the TARGIT group relative to the EBRT group at year 1 (OR 2.07, 95 % CI 1.12–3.85, p = 0.021) and year 2 (OR 2.11, 95 % CI 1.0–4.45, p = 0.05). Following a totally objective assessment in a randomised setting, the aesthetic outcome of patients demonstrates that those treated with TARGIT have a superior cosmetic result to those patients who received conventional external beam radiotherapy.     

Enhancing targeted radiotherapy by copper(II)diacetyl- bis(N4-methylthiosemicarbazone) using 2-deoxy-D-glucose

Most cancer deaths are a consequence of resistance to conventional chemotherapy and radiation therapy. This may be attributable to unique phenotypic characteristics of solid tumors. We have exploited two well-described characteristics of solid tumors commonly associated with treatment failure, high glucose use and hypoxia, to design a unique therapy based on the selective accumulation of two cytotoxic compounds, 2-deoxyglucose (2-DG) and copper(II)diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM). (64)Cu-ATSM localizes to hypoxic regions of tumors and has been used for administering a high local dose of radiation therapy after uptake by cells. 2-DG, a glucose analog, selectively accumulates in cancer cells and interferes with energy metabolism, resulting in cancer cell death. 2-DG has been shown to potentiate the cytotoxic effect of ionizing radiation and certain chemotherapeutic agents. We have tested the effect of 2-DG on tumor response when combined with (64)Cu-ATSM in a mouse breast tumor model using the highly aggressive mouse mammary carcinoma cell line EMT-6. 2-DG administered up to 2 mg/g of body weight daily resulted in no weight loss or systemic symptoms. EMT-6 mammary tumors had similar uptake of [(18)F]fluoro-2-deoxyglucose before and after 2 weeks of 2-DG treatment as determined by microPET imaging, indicating that resistance to 2-DG uptake does not develop. Pretreatment of tumor-bearing mice with 2-DG resulted in increased uptake of (64)Cu-ATSM by tumors compared with nontreated mice. This effect was not observed with the nonhypoxia-specific agent copper(II)pyruvaldehyde-bis(N(4)-methylthiosemicarbazone. When 2-DG was combined with a single dose of (64)Cu-ATSM (2 mCi), tumor growth was inhibited approximately 60% compared with untreated mice, and animals survived approximately 50% longer than untreated mice or animals treated with each agent alone (32 versus 20 days). The maximum effect on tumor growth and survival was observed when 2-DG was administered daily for the lifetime of the mouse. Our results indicate that 2-DG potentiates the effect of (64)Cu-ATSM on tumoricidal activity and animal survival. We hypothesize that 2-DG alters the metabolic state of the cell, leading to increased uptake of (64)Cu-ATSM by the tumor. This would result in a higher local dose of radiotherapy. The continued presence of 2-DG would then prevent the repair of damaged cells, leading to inhibition of tumor growth. Our data indicate that the strategy of combining tumor-specific cytotoxic agents that function by differing mechanisms can result in an effective, selective, tumor-specific cell death with minimal effect on the host.