Js Vaidya

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).

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial

BACKGROUND The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. 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.

Omission of nitrous oxide during anesthesia reduces the incidence of postoperative nausea and vomiting - A meta-analysis

Background Postoperative nausea and vomiting are important causes of morbidity after general anesthesia. Nitrous oxide has been implicated as an emetogenic agent in many studies. However, several other trials have failed to sustain this claim. The authors tried to resolve this issue through a meta-analysis of randomized controlled trials comparing the incidence of postoperative nausea and vomiting after anesthesia with or without nitrous oxide. Methods Of 37 published studies retrieved by a search of articles indexed on the MEDLINE database from 1966 to 1994, 24 studies (26 trials) with distinct nitrous-oxide and non-nitrous oxide groups were eligible for the meta-analysis. The pooled odds ratio and relative risk were calculated. Post hoc subgroup analysis was also performed to qualify the result. Results The pooled odds ratio was 0.63 (0.53 to 0.75). Omission of nitrous oxide reduced the risk for postoperative nausea and vomiting by 28% (18% to 37%). In the subgroup analysis, the maximal effect of omission of nitrous oxide was seen in female patients. In patients undergoing abdominal surgery and general surgical procedures, the effect of omission of nitrous oxide, although in the same direction, was not significant. Conclusion Omission of nitrous oxide reduced the odds of postoperative nausea and vomiting by 37%, a reduction in risk of 28%.

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

INTRODUCTION We believe that conservative treatment of early breast cancer may not require radiotherapy that encompasses the whole breast. We present here the clinico-pathological basis for this view, as well as a novel therapeutic approach that allows intra-operative radiotherapy to be safely and accurately delivered to the target tissues in a standard operating theatre. THE RATIONALE: Whole-organ analysis of mastectomy specimens reveals that 80% of occult cancer foci are situated remote from the index quadrant. In contrast, over 90% of local recurrences after breast conservative therapy occur near the original tumour, even when radiotherapy is not given. Therefore, the remote occult cancer foci may be clinically irrelevant and radiotherapy to the index quadrant alone might be sufficient. A NOVEL TECHNIQUE: The Photon Radiosurgery System (PRS) is an ingenious portable electron-beam driven device that can typically deliver intra-operative doses of 5-20 Gy, respectively, to 1 cm and 0.2 cm from the tumour bed over about 22 min. The pliable breast tissue--the target--wraps around the source, providing perfect conformal radiotherapy. Being soft X-rays, the dose attenuates rapidly (alpha approximately 1/r3), reducing distant damage. RESULTS In our pilot study of 25 patients (age 30-80 years, T = 0.42-4.0 cm), we replaced the routine post-operative tumour bed boost with targeted intra-operative radiotherapy. There have been no major complications and no patient has developed local recurrence, although the median follow-up time is short, at 24 months. CONCLUSION It is safe and feasible to deliver targeted intraoperative radiotherapy (Targit) for early breast cancer. We have begun a randomised trial--the first of its kind--comparing Targit with conventional six-week course of radiotherapy. If proven equivalent in terms of local recurrence and cosmesis, it could eliminate the need for the usual six-week course of post-operative radiotherapy.

Multicentricity of breast cancer: whole-organ analysis and clinical implications

We studied the spatial relationship within the breast between multicentric foci (MCF) and the primary tumour in 30 modified radical mastectomy specimens using Egans correlated pathological-radiological method using 5 mm slices of the whole breast. The relative positions within the breast of the primary tumour and MCF were used to calculate the relative distribution of primary tumour and MCF in the four quadrants of the breast and the per cent breast volume that would be required to be excised to include all MCF. Nineteen (63%) breast harboured MCF. The relative distribution of primary tumour and MCF in the four breast quadrants was significantly different (P = 0.034). MCF were present beyond the index quadrant (25% of breast volume including the tumour) in as many as 79% (15/19) of breasts that harboured MCF; and in half the cases (15/30) when all breast were considered. This is in variance with the suggestion put forward previously that MCF are contained within the index quadrant in 90% of cases. Although the number of patients in the present series is small, the probability of our finding being due to play of chance is 1 in 1500. In a large series of breast conservation studies > 90% of early breast recurrences have been found to occur in the index quadrant. Our finding, that in half the patients (15/30) MCF are present in quadrants other than the index quadrant, suggests that MCF do not give rise to early breast recurrence.

Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding

Purpose: After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be implicated. The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment. Experimental Design: We studied how normal and mammary carcinoma cell growth and motility are affected by surgical wound fluids (WF), collected over 24 h following breast-conserving surgery in 45 patients, 20 of whom had received additional TARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed. Results: WF stimulated proliferation, migration, and invasion of breast cancer cell lines. The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients. Conclusions: Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.

Prediction of nipple and areola involvement in breast cancer

AIMS To find a pre-operative test for nipple and areola involvement in breast cancer. METHODS Areola-tumour distance was measured in 140 consecutive patients (median age 45, range: 23-83) undergoing a mastectomy. We analysed whether nipple and areola correlated with areola-tumour distance, tumour size, nodal status, perinodal involvement and lymphatic embolization. RESULTS The nipple was involved in 22 (16%) cases and this correlated with tumour size, number of lymph nodes, perinodal extension and presence of lymphatic emboli. In all these 22 cases, the tumour was within 2.5 cm of the areola. Tumour size, however, could not predict nipple involvement in tumours within 2.5 cm of the areolar edge. CONCLUSIONS In the one-fifth of cases where the tumour is over 2.5 cm from the areola, preserving the nipple and areola for reconstruction may be worthwhile. In remaining cases, some other predictive test for nipple involvement would be necessary.

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.

Does breast cancer exist in a state of chaos

INTRODUCTIONÐMODELS OF DISEASE Throughout the history of medicine mankind has demonstrated extraordinary feats of imagination in elaborating hypothetical models to explain the nature of disease. These models then suggest therapeutic strategies to influence the natural history of disease processes. Until the early 17th Century in Western medicine and to this day in classical Chinese medicine these models were largely metaphysical [1]. However, Ayurveda, the Indian system of medicine, is based on a dynamic balance between three principles: combustion/ energy-production/anabolism (Pitta), transport/communication (Vaata), and excretion/catabolism (Kapha). Disease was supposed to be a manifestation of the disturbance of this balance and the doctors duty was to maintain and restore this balance [2]. In the last century or so models of disease have progressed from the mechanical to the biological and more recently to the mathematical. The change of allegiance from one model to another has been likened to a Kuhnian revolution or paradigm shift [3]. The two most famous in the history of medicine were the overthrowing of the Gallenic doctrine by William Harveys description of the circulation of the blood and the replacement of the miasma theory of infection by the bacterial theory of infection which ultimately led to the success of anti-microbial therapy.

Role of ultrasonography to detect axillary node involvement in operable breast cancer

Prompted by the concern about unnecessary axillary dissections, we prospectively studied the accuracy of clinical examination (CE) and conventional ultrasonography (USG, 7.5 MHz), to diagnose pre-operatively metastatic axillary lymph nodes in 200 operable breast cancer patients. USG had higher specificity (90% vs 77%, P = 0.025) and higher positive predictive value (ppv = 90% vs 76%, P = 0.02) than CE. Together, CE + USG had higher sensitivity (82% vs 58%, P = 0.00005) and higher negative predictive value (npv = 76% vs 58%, P = 0.008) than CE alone. In women < 45 years, CE + USG had higher sensitivity (91% vs 76%, P = 0.037) and npv (89% vs 67%, P = 0.018) than in older women. The sensitivity and npv of CE + USG to detect > 1 positive node were 97% (for both) in women < 45 years compared to 81% and 79% in older women. The high sensitivity of CE + USG (82% for the whole group) is probably due to the higher proportion of young women (median age = 45) in our population. It suggests that using CE + USG to avoid axillary dissection in some patients is feasible.