Electrons for intraoperative radiotherapy in selected breast-cancer patients: late results of the Montpellier phase II trial

Between November 2004 and November 2007, 96 women accepted to participate in the RADELEC phase II trial evaluating IORT delivered to the tumor bed as exclusive radiotherapy. Inclusion criteria were T1N0M0 [6] unifocal ductal invasive carcinoma (biopsy-proven) with positive (> 10%) estrogen receptors, non-metastatic disease, and age ≥ 65 years old. No extensive intraductal (EIC) or lymph vessel invasion had to be identified on primary biopsy.

Local evaluation (mammography and breast ultrasound) evaluated precisely the diameter of the tumor (MRI was optional). Lobular tumors were excluded due to the risk of multifocality. Neoadjuvant treatments were not allowed before surgery.

The detailed procedure was described in a previous article [7]. Briefly, IORT modalities included a dedicated linear accelerator (Saturne 43, Varian, France) located centrally between the six operating theaters. Lumpectomy was performed with an incision centered on the tumor or periareolar in outer or inner/medial lesions, respectively. Tumor-free margins of at least 2 mm were assessed by frozen sections. Axillary lymph node dissection was performed using a sentinel lymph node procedure in all cases. Nodes were analyzed by intraoperative imprint cytology. The tissue surrounding the excision cavity was then mobilized and approximated by sutures to bring it into the radiotherapy planning target volume. The radiation oncologist identified visually the tumor bed and, together with the surgeon, measured the depth of the tissue to be irradiated. A semi-conductor detector (PTW) was placed in the middle of the tumor cavity and fixed to proceed to an in vivo dosimetry. The applicator tubes were then placed under visual control. The entire tumor bed was strictly encompassed customarily with a 20-mm margin using 40–60 mm diameter flat-ended brass applicators. Complete skin sparing was verified in each case.

The treatment was delivered at using electrons with an energy ranged between 6 and 9 MeV, in accordance with the thickness of breast tissue to be treated. All patients received 21 Gy, prescribed and specified at the depth of the 90% isodose line, which was defined as the optimal and maximal tolerated dose level [8].

Patients were seen three weeks after IORT for the first medical follow-up and were prescribed adjuvant treatment according to our guidelines. Postmenopausal women who were shown to have estrogen receptor and/or progesterone receptor-positive tumors (ER and/or PR = 10% of the tumor cells positive by an immunocytochemical assay) were prescribed an aromatase inhibitor in front line or sequentially after two years of tamoxifen. No adjuvant chemotherapy was initially planned in this setting i.e. T1N0M0 and age ≥ 65 years old.

Long term cosmetic results were yearly performed by the surgeons and the radiation oncologists with clinical exams, systematic photographs (two pictures with frontal and profile views), and a local questionnaire filled in independently by the patient and the physician. We considered the breast shape and position, the areola shape, and the presence or absence of telangiectasia.

This phase II trial was conducted using a two-stage optimum Simon design with forty-two eligible patients required for evaluation of the primary endpoint defined as IORT reproducibility using the quality index (QI) comparing prescribed and the in vivo measured doses [7].

Data were summarized by frequency and percentage for categorical variables, and by means, standard deviations, median, and range for continuous variables. Updated median follow-up was obtained with the reverse Kaplan-Meier method.

All survival events were measured from the day of surgery to event (assessed by clinical exam, mammography, or breast ultrasound). Disease-free survival (DFS; event was locoregional/distant recurrence or death) and overall survival (OS; event was death) rates were estimated according to the Kaplan-Meier method.

Cohen's kappa coefficient was used to measure inter-rater agreement for qualitative items [9]. A κ less than 0 is a disagreement, from 0.0 to 0.20 is a very poor agreement, from 0.21 to 0.40 is a poor agreement, from 0.41 to 0.60 is a moderate agreement, from 0.61 to 0.80 is a strong agreement, and from 0.81 to 1.00 is an almost perfect agreement.

Analyses were performed using STATA 11.0.

Among the 42 patients, 36 procedures were assessable and 35 were measured as acceptable according to the primary endpoint (97%). The median measured dose was 23 Gy (range, 19.6–26.5 Gy), with a high concordance with the prescribed dose (21 Gy at the 90% isodose, corresponding to 23 Gy at the 100% level).

Among the 94 patients who accepted to participate in this trial and signed the informed consent before the surgical procedure, 11 patients were treated by IORT but were secondary excluded of the final analysis due to the definitive pathologic report. The reasons of non IORT delivery were detailed for 41 patients in Lemanski et al. [7]. Finally, 42 patients were included in the RADELEC trial according to the study criteria.

Clinical breast parameters and tumor characteristics were reported before [7]. Briefly, the median tumor size was 10 mm (range 3–19), SBR I-II grade concerned 36 tumors (86%), and 100% of the tumors expressed estrogen receptors. According to our national guidelines, no chemotherapy was indicated for these T1N0 hormone-relevant tumors and adjuvant hormonal treatment was started within the first month for all patients.

No immediate severe side-effect was observed during the IORT procedure. At discharge, three acute wound complications, one infection, five haematoma, and six moderate local pains. None of them necessitated secondary intervention [7].

All included patients are still alive with a median follow-up of 72 months (range 66–74, Figure 1). The 5-year-disease free survival is 92.7% (range 79.1−97.6).

Among the 42 included patients, four experienced a local event. Three were defined as ipsilateral breast tumor relapses (IBRT) according to the Royal Marsden criteria [10] i.e. in the same quadrant as the primary tumor, with the same histology and similar or higher grade. These true relapses occurred within the initial tumor bed but relatively delayed after the IORT procedure (25, 54, and 60 months). The two first were 18 and 2 mm ductal unifocal carcinomas. The latter one was considered as a more aggressive relapse identified by five isolated micropapillar tumors but identical to the initial histology.

The fourth local event was a second 3-mm primary ductal carcinoma located in another quadrant and diagnosed 3 months after the surgery. The RADELEC scientific committee considered this event as a second primary tumor omitted during the preoperative staging (staged only by ultrasound).

These four patients underwent standard salvage mastectomy and all restarted a new hormonal treatment for five years more. None received any chemotherapy.

The eleven patients who received IORT but excluded after the definitive pathology results were also followed within the time frame. None of them presented a local recurrence and all are still alive without any disease.

Post-treatment mammograms showed characteristic pictures of severe cytosteatonecrosis in 30 patients (71%) corresponding to a palpable mass within the IORT area for 17 patients (40%). These structural changes in the tumor bed complicated the evaluation of mammograms within the first two years of follow-up. Two patients required non-routine procedures leading to a biopsy for pathological control. Both of them had outside institution exams.

Ten patients (24 %) reported late grade 1 breast pain. One patient experienced a rib fracture 14 months after the IORT procedure. Globally, 41 among the 42 treated patients (98%) disclaimed a totally satisfaction of IORT and would recommend the procedure.

The 5 year-cosmetic evaluation, including clinical examination and systematic photographs reviewed by 2 physicians showed good to excellent results and are presented for 4 patients in Figures 2, 3, 4 and 5. These photographs showed excellent results whatever the size of the breast (Figure 2, 3, 5). For inferior tumors, scar retraction seems to be higher (Figure 4) but could not be directly attributed to the IORT procedure. The 1, 2, 3, 4, and 5-year cosmetic results were auto-evaluated by patients and by physicians with 97.5% compliance. The results were good and are detailed in Tables 1 and 2. Overall, a poor agreement was observed between patients and physicians about breast size, nipple position, and scar appearance at all evaluation time. In addition, a very poor agreement was observed between patients and physicians about telangiectasia and global cosmetic result whatever the time of evaluation. Regarding breast shape, we observed a poor agreement, a disagreement, and a very poor agreement at 24, 48, and 60 months, respectively. A moderate agreement was observed about nipple shape at 24 months (Table 3). After pooling variables items in two categories (no/small difference vs. middle/high difference), the agreement Kappa coefficient is improved for breast size at 24 and 60 months (0.46 and 0.60, respectively). For breast shape, we observed a strong agreement at 24 and 60 months (0.63 for both) and a perfect agreement for nipple position and nipple shape at 60 months.