Intraoperative Radioterapy in Breast Cancer

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Introduction: Breast cancer is the leading malignant neoplasm in women, registering the highest female incidence and mortality worldwide. According to the World Health Organisation, the highest incidences (80-90 cases/100,000 women) are to be found in developed countries, such as the USA, Australia and Europe (northern and western). It is estimated that one out of every ten women will develop breast cancer over her lifetime, with the most advanced cases occurring among adult women aged over 50 years and risk increasing linearly with age. At a European level, the probability of developing breast cancer before reaching 75 years of age is put at 8%. Prognosis of patients with breast cancer depends on tumour size and spread, and the presence of metastasis in regional or distal lymph nodes. Survival rates have gradually improved, rising to figures of 85% thanks to improvements in screening and treatment. Radiotherapy has shown itself to be an essential part of combined cancer treatment. Indeed, recent decades have witnessed a growing interest in radiotherapy techniques designed to treat only the portion of the breast deemed to be at greatest risk of developing local relapse, since approximately 85% of local recurrences occur in the proximity of the primary tumour within the first 5 years of diagnosis. Progress in radiotherapy techniques has allowed for the application of technically more sophisticated treatments, based on the philosophy of administering higher doses of effective radiation without increasing the incidence of adverse effects, inasmuch as sensitive structures are mobilised and shielded when radiation is administered. Such techniques include intraoperative radiotherapy (IORT), which seeks to improve local control of the disease by visual and direct administration of a high dose of radiation at the time of surgery, thereby enabling dosages to be increased and healthy tissue preserved.
Objectives: The principal objectives of this report were: to assess the efficacy, effectiveness and safety of IORT in patients with breast cancer, in terms of survival and local control of the disease; and to ascertain its impact on the quality of life of such patients.

Methods: A systematic review of the scientific literature published until October 2009 was conducted in the following databases: (a) specialised systematicreview databases, such as Health Technology Assessment (HTA), Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Plus Library; and, (b) general databases, such as Medline, Embase, ISI Web of Knowledge (Institute for Scientific Information) and Índice Médico Español (IME). To complete this process, we also: consulted the databases of the US National Institute of Health ( and international registers such as Current Controlled Trials (CCT) and Tripdatabase; conducted a general search of quality Internet web pages (organisations, scientific societies, etc.); and carried out a manual review of the references cited in the studies included. Two independent, blinded reviewers examined and selected the papers separately in accordance with preestablished inclusion and exclusion criteria. This information was then summarised in evidence tables. Study quality was assessed by both researchers, using a specific scale specially adapted for the purpose.

Results: The bibliographic search retrieved 394 studies. Of these, 14 that met the selection criteria were included. No study displayed a comparative design. Three systematic reviews were located, and the remainder were case-series studies. While most of the studies included patients in the initial stages of breast cancer (T0-T2), some also evaluated T3. IORT dosages ranged from 10Gy to 24Gy, with these being combined with subsequent administration of external beam radiation therapy (EBRT) (dosages of 45Gy-50Gy in most cases). Two studies exclusively administered IORT without postoperative EBRT, and used the highest IORT doses (20Gy to 24Gy). Overall local control of the disease surpassed 98% at 1 and 4 years, and overall survival was 99% at 5 years and 90.9% at 7 years. In the case of those studies that exclusively used IORT, local control of the disease was approximately 98% at 2-4 years, and overall survival was 99% at 2 years, though the latter finding was based on only one study. Toxicity was assessed using the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) and Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic (LENT/SOMA) scales. Insofar as acute complications were concerned, most were mild-tomoderate (grades 0-2) and cutaneous in nature (fibrosis, skin retraction and atrophy), though there were also cases of necrosis, telangiectasia or moderate pain (grades 2-3). Incidence of severe chronic complications was low, though mention should be made of one case of grade IV necrosis; in all the remaining cases, they were mainly mild-to-moderate, with the most frequent being fibrosis, whether localised or affecting the whole breast, and dermatologicaltype complications (changes of pigmentation, retraction or atrophy). There were also cases of pain, oedema and infection.

Discussion: Most of the studies assessed the efficacy of the association between IORT and EBRT for treating the initial stages of breast cancer in low-risk patients with invasive tumours of a size not exceeding 2-3 cm. No study assessed stage T4, and only two studies analysed stage T3. The remaining studies considered stages T1-2, reporting local control of the disease of over 98% at 4 years and incidence of distal metastases of 5% at 4 years. The studies, albeit few in number, that exclusively used IORT as the sole radiotherapy treatment, reported local control of the disease of 99% at 2 years, declining to 95% at 4 years. Toxicity results were assessed using different grading scales, principally the RTOG/EORTC and LENT-SOMA scales, and though this might constitute one possible limitation of this report, good correlation was nevertheless observed between the two scales in the case of late toxicity. Incidence of acute complications did not exceed 9%, though some studies reported higher incidences of close on 60%: these were mainly mild-to-moderate in nature, with dermatological reactions (fibrosis, oedema, erythema or fat necrosis) prevailing. The studies that used IORT as sole radiotherapy treatment (21-24Gy) reported the lowest incidences of acute complications, though these data were based on a small number of studies. The most severe chronic complications (grade 3), such as fibrosis and skin alterations (pigmentation changes or telangiectasia) were associated with the highest radiation dosages (24Gy). Women treated with doses of 24Gy developed grade-3 fibrosis in 30% of cases, with incidence declining sharply as dosage was reduced (2% with 20Gy). When radiological (mammography and echocardiography) results of IORT (22Gy-24Gy) were compared against those of EBRT, IORT was observed to result in a higher number of structural distortions and oedema, and these differences became especially evident after 12 months with the addition of necrosis and calcifications.

Conclusions: Despite the fact that there is little evidence of the use of IORT in breast cancer and that the studies available are of low quality, patients treated with IORT appear to display a slightly better survival rate than do patients to whom other therapies are administered. Moreover, IORT would seem to be a relatively safe technique, since the adverse effects observed are comparable to those of treatment with external radiotherapy.