Recent recommendations regarding indications of accelerated partial breast irradiation (APBI) have been put forward for selected breast cancer (BC) patients. However, some treatment planning parameters, such as total dose, are not yet well defined. The Institut Gustave Roussy has initiated a dose escalation trial at the 40 Gy/10 fractions/5 days and at a further step of total dose (TD) of 42 Gy/10 fractions/ 5 days. Here, we report early results of the latest step compared with the 40 Gy dose level.
Methods and materials
From October 2007 to March 2010, a total of 48 pT1N0 BC patients were enrolled within this clinical trial: 17 patients at a TD of 42 Gy/10f/5d and 31 at a TD of 40 Gy/10f/5d. Median follow-up was 19 months (min-max, 12–26). All the patients were treated by APBI using a technique with 2 minitangents and an “enface” electrons delivering 20% of the total dose. Toxicities were systematically assessed at 1; 2; 6 months and then every 6 months.
Patients’ recruitment of 42 Gy step was ended owing to persistent grade 3 toxicity 6 months after APBI completion (n = 1). Early toxicities were statistically higher after a total dose of 42 Gy regarding grade ≥2 dry (p = 0.01) and moist (p = 0.05) skin desquamation. Breast pain was also statistically higher in the 42 Gy step compared to 40 Gy step (p = 0.02). Other late toxicities (grade ≥2 fibrosis and telangectasia) were not statistically different between 42 Gy and 40 Gy.
Early toxicities were more severe and higher rates of late toxicities were observed after 42 Gy/10 fractions/5 days when compared to 40 Gy/10 fractions/5 days. This data suggest that 40 Gy/10 fractions/ 5 days could potentially be the maximum tolerance for PBI although longer follow-up is warranted to better assess late toxicities.
Keywords:3D-conformal accelerated partial breast irradiation; Dose escalation
The current trend in early breast cancer (BC) is to shorten overall treatment time either by hypofractionated whole breast irradiation  or by accelerated partial breast irradiation (APBI). Local control efficacy of 3D-conformal APBI compared to whole breast irradiation is currently investigated through large clinical trials, such as NSABP B-39/ RTOG-0413 phase III trial  and RAPID trial . Waiting for definitive results of those clinical trials, the American and European Radiation Oncology Societies (ASTRO and ESTRO) put forward guidelines for selected group of patients with breast cancer at low risk of local relapse for whom APBI could be performed out of clinical trials [4,5]. Even though 3D-conformal APBI is one of the most used APBI technique due to its practicality , the optimal total dose and fractionation is not yet well defined. A dose escalation 3D-conformal APBI trial has been initiated in 2003 at the Massachussetts General Hospital (MGH) to assess the optimal total dose consisting in delivering 32 Gy/8fractions (f) over 4 days; 36 Gy/9f over 4½ days; 40 Gy/10f over 5 days (“40 Gy step”). In collaboration with the MGH, we extended this clinical trial by the enrolment of patients in the 40 Gy step  and in an additional and further step : 42 Gy in 10 BID fractions over 5 days. We have recently reported the 40 Gy step ((7)) and here, we report early results of the latest step comparing 42 Gy/10 f with the 40 Gy/10 f dose level.
Methods and materials
From October 2007 to March 2010, 48 pT1N0 unifocal BC patients were prospectively enrolled in an institutional and national review board-approved phase II trial. Patients eligibility has been already described in  and they were treated 4 to 12 weeks after a breast conservative surgery with 3D-conformal APBI.
Stopping rules were any persistent and severe (grade 3) toxicities (fibrosis or fat necrosis) or persistent early grade 3 toxicity occurring during the year that followed APBI completion. 31 breast cancer patients were enrolled in the 40 Gy step; and only 17 breast cancer patients in the 42 Gy step. Hence, per the trial stopping rules, patients’ recruitment was ended owing to persistent grade 3 toxicity 6 months after APBI completion (n = 1).
Treatment planning and toxicity assessment
Briefly, all patients underwent to computed tomography (CT)-based 3D planning. The ipsilateral and contralateral breast, left and right lungs and heart were contoured . The clinical target volume (CTV) was defined as the delineation of the visible lumpectomy cavity and the surgical clips placed inside the lumpectomy cavity [9-11]; planning target volume (PTV) as a CTV expansion of 2.3 to 2.8 cm. The PTV for evaluation (PTV_EVAL) was the PTV with exclusion of the anterior chest wall/pectoralis muscles and the first 5 mm of tissue under the skin and anterior chest wall/pectoralis muscles (according to the definition by Vicini et al. ). The technique used was a combination of photon beams of 6 MV and electrons of 6 to 22 MeV. The dosimetric plan was performed using Dosigray 188.8.131.52 TPS (Dosisoft) . Normal tissue dose–volume constraints were defined as followed: 50% of the non-targeted breast volume had be less than 50% of the prescribed dose; the PTV_EVAL-to-whole breast ratio had to be less than 25%; and a limited dose was to be received by heart and lungs. The lung volume dose constraints used were as follows: <3% at 20 Gy, <10% at 10 Gy, and <20% at 5 Gy . Two successive total doses were prospectively assessed: 40 Gy in 10 BID fractions over 5 days and 42 Gy in 10 BID fractions over 5 days, with a minimum interfraction interval of 6 hours.
Patients and tumors characteristics were compared with the Wilcoxon test between each steps (40 Gy and 42 Gy). Dosimetric data of 40 Gy and 42gy steps were compared with the Wilcoxon test.
Initial toxicities assessment was performed before APBI; then 1, 2, 6 months after APBI completion and further every 6 months. Toxicities were scored according to the RTOG scale: grade 0 for none; grade 1 for mild; grade 2 for moderate; grade 3 for severe; and grade 4 for fatal toxicities. Toxicities incidences (by type and global), estimated for each of the 2 total doses, were plotted with Kaplan Meier incidence curves and compared with a log-rank test.
Patients and tumor characteristics are listed in Table 1. Median follow-up was 19 months (min-max, 12–26) in the 42 Gy step vs 32 months (min-max, 23–40) in the 40 Gy step. Mean age was 67 years (min-max, 52–76). Median tumor size was 10 mm (min-max, 4–20). Enrolled patients had mainly pT1N0 invasive ductal carcinoma (82%), positive hormone receptors, negative Her2 overexpression.
Table 1. Patients and tumor characteristics (Abbreviation: ER = estrogen receptor; PR = progesteron receptor)
Planning target volume and normal tissue dosimetry
PTV_EVAL coverage was adequate with a mean dose to the PTV_EVAL at 43.7 Gy (range, 43.1 – 44.4 Gy). Mean breast V20Gy was at 41.6% (range, 15.4% – 55.2%). Mean non-target breast V42Gy and V20Gy were at 6% (range, 1.6%–11.9%) and 30.9% (range, 12.5%-44.5%), respectively. Mean ipsilateral lung dose was 1.4 Gy (range, 1.0–1.8 Gy), and the V20 Gy was 0.2% (range, 0.0% – 1.0%). The mean heart dose was 1.1 Gy (range, 1.0–1.3 Gy). No significant difference was seen between dosimetric parameters of 40 and 42 Gy steps except for a higher V5Gy in the heart in the 40 Gy step (p = 0.05). Other dosimetric characteristics are listed in Table 2.
Table 2. Dosimetric characteristics at the 42 Gy and 40 Gy step
Table 3. Early and late toxicity
Figure 1. Incidence of grade ≥2 toxicities
Although patients cohort is smaller than those in 40 Gy step, patients had more grade 2 erythema two months after APBI completion (n = 6/17; p = 0.14), but was not statistically significant when compared to 40 Gy step. On the contrary, patients who were enrolled in the 42 Gy step had statistically more grade 2 moist desquamation (p = 0.05); and had statistically more grade 2 dry desquamation (p = 0.01) at early time points (1 and 2 months after APBI completion).
Late toxicities increased with higher total dose and occurred earlier (at 6 months). Grade ≥ 2 telangiectasia were observed at 6 months in 2/17 (12%) of patients in the 42 Gy versus 1/31 (3.2%) for the 40 Gy and increased with time (30% in the 42 Gy versus 6% for the 40 Gy at 18 months). Grade ≥ 2 breast fibrosis was observed in 2/31 (6.5%) of 40 Gy-patients and in 4/17 (24%) of 42 Gy-patients at 6 months. Similarly, grade ≥ 2 breast fibrosis was reported at 18 months in 3/31 (10%) of 40 Gy-patients and in 3/17 (18%) of 42 Gy-patients. Hence, cosmetic results assessed by physicians were considered as fair in 3/13 patients at 18 months in the 42 Gy step whereas in the 40 Gy step was 2/26 patients. However grade ≥2 toxicities between 40 Gy and 42 Gy steps were not statistically different except for breast pain (p = 0.02). Patients treated at the 42 Gy step indeed observed more grade ≥2 breast pain (3/17 patients) rather than those treated at the 40 Gy step (4/31 patients), the difference was statistically significant (p = 0.02).