Abstract
Background
Still controversial is the optimal radiotherapy (RT) schedule for high-risk patients after mastectomy or breast conserving surgery (BCS). An alternative to conventional RT schedules is hypo-fractionation (HF) (40.5 Gy or 42.67 Gy in 15–16 fractions). The present observational, retrospective study assessed acute and late toxicities after hypo-fractionation targeting the chest wall/breast and regional lymph nodes, compared with a cohort that had received conventional fractionation. The aim was to establish the safety of hypo-fractionation in wide-field irradiation.
Materials and methods
This study enrolled 80 patients (median age 63 years; range 34–83) who underwent either BCS (9) or mastectomy (71) as well as axillary lymph node dissection. The RT schedule was 40.05 Gy in 15 fractions over 3 weeks. A simultaneous integrated boost (SIB) (49.5 Gy in 15 fractions) was delivered to the tumour bed in 9 patients who received whole breast irradiation (WBI). Acute and late toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE v4.02) and compared with outcomes in 51 patients after conventionally fractionated RT to the chest wall/breast and regional nodes. Median follow-up was 16 months (range 2.7–33.8 months).
Results
All patients completed RT with no toxicity-related interruption. No patient developed any cardiac or pulmonary toxicity or ≥ grade 3 acute skin and oesophageal toxicity. Late G1 skin toxicity occurred in 9/75 patients who were eligible for analysis. No patient developed ≥ G2 late toxicity. The incidences of acute toxicity, skin rash and dysphagia were significantly lower after HF (p < 0.001 and 0.040, respectively). No significant differences emerged in late edema and skin toxicity.
Conclusions
The efficacy and safety of hypofractionated regimens were confirmed in real-life settings. Present evidence supports the use of HFRT as standard treatment, providing patients with the advantages of shorter treatment times and reduced healthcare costs.
Keywords: breast cancer, LINAC-based IMRT, regional node irradiation, tomotherapy, hypofractionated radiotherapy
Introduction
Standard treatment for patients at high-risk of relapse after mastectomy or breast conserving surgery (BCS) is radiation therapy (RT) to the chest wall/breast and regional lymph nodes. Effective though it is, the optimal RT schedule is still controversial. Even though conventional fractionation (CF) is still commonly used to treat the chest wall/breast and regional nodes, hypo-fractionation (HF) (40.5 Gy or 42.67 Gy in 15–16 fractions) is supported by recommendations [1, 2] based on results of clinical studies and radiobiological studies indicating that breast cancer cells may be more susceptible to high radiation doses per fraction [3]. In clinical trials exploring HF, most patients underwent whole breast irradiation (WBI), so few data are available on chest wall and regional nodal irradiation (RNI). Furthermore, when breast reconstruction is performed, HF might have the potential for severe treatment-related toxicity [4].
The present retrospective observational study evaluated acute and late toxicities after moderate HF targeting the chest wall/breast and regional lymph nodes and compared toxicity outcomes with a cohort that had received CF. The overarching goal was to establish the safety of the hypo-fractionated regimen in wide field irradiation.
Materials and methods
From January 2019 to July 2021 this study enrolled 80 consecutive patients (median age 63 years; range 34–83). They underwent BCS (9; 11.25%) or mastectomy (71; 88.75%). All underwent axillary lymph node dissection (ALND). Reconstruction was performed in 39/71 (15 with prostheses and 24 with expanders). Six mastectomized patients were treated because of chest wall relapse. Patient and tumour characteristics, as well as adjuvant/neoadjuvant systemic therapies are shown in Table 1.
Table 1.
Patient and tumour features
| Characteristics | No. patients (%) |
|---|---|
| Age [years] | Median (range): 61 (34–86) |
| Body mass index | 25.75 (range 18.4–35.8) |
| Comorbidity | |
| Hypertension | 31 (38.75%) |
| Hypercholesterolemia | 12 (15%) |
| Hypothyroidism | 10 (12.5%) |
| Systemic therapy | |
| CHT Neoadjuvant | 12 (15.15%) |
| CHT Adjuvant | 40 (50%%) |
| Trastuzumab | 29 (36.25%) |
| Surgery | |
| BCS + ALND | 9 ( 11.25%) |
| Mastectomy + ALND | 71 (88.75%) |
| Other (local excision or only ALND) | 6 (7.5%) |
| Stage | |
| ≤ IIB | 65 (81.25%) |
| > IIB | 9 (11.25%) |
| Hormone receptors | |
| Positive hormone receptors | 53 (66.3%) |
| Her2 Express | 29 (36.5%) |
| Histology | |
| Ductal | 66 (82.5%) |
| Lobular | 14 (17.5%) |
| Grading | |
| G1 | 6 (7.5%) |
| G2 | 28 (35%) |
| G3 | 46 (57.5%) |
| RT Site | |
| Right | 46 (57.5%) |
| Left | 34 (42.5%) |
ALND — axillary lymph nodes dissection; BCS — breast conserving surgery; CHT — chemotherapy; ER/PgR — estrogen/progesterone receptors; LN — lymph nodes
Acute and late toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE v4.02). Toxicity data were compared with a series of 51 patients who had received conventionally fractionated RT to the chest wall/breast and regional nodes.
The study was conducted in accordance with the 1975 Helsinki Declaration, as revised in 2000, and all patients provided written informed consent.
Treatment procedures
Free breathing CT scans without contrast medium were acquired (2.5 mm slice thickness). All patients lay in a supine position for the treatment, with both arms raised over the head. A “Breast Board” was used as immobilization system. All CT scans were sent to the Pinnacle3 treatment planning system V9.8 (Philips Radiation Oncology Systems, Fitchburg, WI). Clinical target volumes (CTVs) and organs at risk (OARs) of toxicity were contoured on each scan. CTVs were the whole breast or the chest wall plus level III and IV regional lymph nodes, as well as the undissected axillary area in 78 patients and the chest wall in 1. Contouring followed Italian guidelines. Contoured OARs were the lungs, heart, contralateral breast, spinal cord, oesophagus, larynx, thyroid, humeral head.
The RT schedule was 40.05 Gy in 15 fractions over 3 weeks. A simultaneous integrated boost (SIB) (49.5 Gy in 15 fractions) was delivered to the tumour bed in 9 patients who received WBI.
An intensity-modulated radiotherapy (IMRT) with 6 MV photons was used to treat all patients: 38 with 5 equally spaced coplanar beams, using a linear accelerator (linac; Varian DHX MLC (Varian Medical Systems)) and 42 with an helicoidal technique, as delivered by a Tomotherapy HD unit (Accuray, Sunnyvale, CA). A 0.5 cm physical bolus tissue equivalent was used in 9 patients to increase skin dose.
Statistical analysis
As the Shapiro-Wilk test showed data distribution was asymmetric, the Mann–Whitney U-test was used to compare continuous variables. The Chi-square test with Yates’ correction or Fisher’s exact test compared categorical variables.
All calculations were carried out with IBM-SPSS® version 26.0 (IBM Corp., Armonk, NY, USA, 2019). A two-sided p-value < 0.05 was considered significant.
Results
Median follow-up was 16 months (range 2.7–33.8 months). All patients completed treatment with no toxicity-related interruption. No patient developed any cardiac or pulmonary toxicity or ≥ grade 3 acute skin and oesophageal toxicity. Some patients suffered more than 1 toxicity. Late G1 skin toxicity occurred in 9/75 patients (12%) who were eligible for analysis. No patient developed ≥ G2 late toxicity. Graded toxicities are shown in Table 2.
Table 2.
Treatment-related G1–G2 toxicities in 80 patients
| Acute toxicities (site) | G1 No. (%) | G2 No. (%) |
|---|---|---|
| Skin | 35 (43.75%) | 4 (5%) |
| Edema | 5 (6.25%) | 2 (2.5%) |
| Fatigue | 1 (1.3%) | 1 (1.3%) |
| Dysphagia | 20 (25%) | 15 (18.8%) |
| Late toxicities (site) | ||
| Skin | 9 (12%) | 0 |
Table 3 reports the dosimetric results; no parameter of which emerged as associated with acute or late skin toxicity. Body mass index and endocrine therapy were not related to acute or late skin toxicity.
Table 3.
Results
| Structure | Parameter | Mean value (range) |
|---|---|---|
| Breast/chest wall | Volume [cc] | 771.93 (range 165.47–2005.02) |
| PTV breast/chest wall | Dmean [Gy] | 40.4 (39.3–48.5) |
| Lymph node | Volume [cc] | 117.13 (range 50.6–273.20) |
| PTV lymph node | Dmean [Gy] | 40.2 (39–41.4) |
| Oesophagus | Dmax [Gy] | 36.55 (16.30–43.60) |
| Dmean [Gy] | 8.11 (5.2–17) | |
| V20 (%) | 12.93 (7–32) | |
| Heart | Dmean [Gy] | 3.13 (0.33–5.24) |
| Ipsilateral lung | V4,8 (%) | 51.82 (4–74) |
| V18 (%) | 17.26 (1–29) | |
| Controlateral lung | V4,8 (%) | 16.33 (10–50) |
| V13,8 (%) | 1.63 (7–21) | |
| Controlateral breast | D2 [Gy] | 6.74 (0.98–13) |
| D50 [Gy] | 2.96 (0.21–8) | |
| Spinal cord | Dmax [Gy] | 18.6 (4–3.88) |
| Larynx | Dmax [Gy] | 28.32 (2.57–41.42) |
| Thyroid | Dmean [Gy] | 23.77 (6–64.35) |
PTV — planning target volume
The mean dose to the oesophagus and the volume of oesophagus receiving 20% or more of the dose (V20) were significantly higher in patients who developed acute dysphagia than in those who did not (p = 0.005 and p = 0.019, respectively).
When the CF was compared with the HF, the incidences of acute toxicity, i.e. skin rash and dysphagia, were significantly lower after HF (p < 0.001 and 0.040, respectively) (Tab. 4). No significant differences emerged in the incidences of late edema and skin toxicity.
Table 4.
Side effects after hypofractionated vs. conventional radiotherapy (RT)
| Side effect | Hypo-fractionated RT (tot 80 pz) | Conventional RT (tot 51 pz) | P |
|---|---|---|---|
| Fatigue | 2(2.5%) | 5 (9.6%) | 0.166 |
| Rush | 39(48.8%) | 46 (88.5%) | 0.000 |
| Edema | 7 (9.6%) | 10 (19%) | 0.482 |
| Dysphagia | 35 (67.3%) | 35 (47.5%) | 0.040 |
| Late skin toxicity | 9 (13.7%) | 1 (5.8%) | 0.257 |
Discussion
The results of our study confirm the safety of HF when delivered to the breast/chest wall and regional nodes. We observed no acute cardiac or pulmonary toxicities and low rates of acute and late skin toxicity, concurring with findings that hypo-fractionated postmastectomy radiotherapy (PMRT) proved non-inferior to conventional fractionated PMRT in terms of loco-regional control, with similar skin reactions in most studies that were analysed in a recent review [5]. Another study [6] found higher acute skin reactions in the HF group, which might be attributed to old Cobalt technique. In the present series, all patients received IMRT treatment, and most underwent Tomotherapy, which was reported to deliver excellent target coverage and homogeneity [7].
Although no significant toxicity emerged in 15 patients undergoing breast reconstruction with implants, the low number precluded drawing conclusions about the cosmetic outcomes of HF. Ongoing trials like the American randomized phase III trial ALLIANCE 221505 may provide valuable insights into this aspect.
Results from the present series were compared with a previous cohort who had been treated with conventional radiotherapy [7]. Significantly lower rates of acute skin rash and dysphagia were observed after HF while no differences emerged in the frequency of late skin toxicity, thus underscoring the potential advantages of hypofractionated regimens in minimizing acute treatment-related morbidity. Favorable acute toxicity profiles with HF were also reported in the Hypobreast trial [8]. In a randomized trial Wang et al. [9] showed no significant differences in acute and late toxicities after conventional or hypo-fractionated RT, but fewer patients in the HF group suffered grade 3 acute skin toxicity (3% vs. 8% p < 0.0001). In the present study, we did not observe any grade 3 toxicity at all.
The incidence of dysphagia was lower in our study than reported by Wang et al. (grade 2: 18.8% vs. 40.09%, and grade 3: 0% vs. 0.3%). Patients with dysphagia had received significantly higher mean doses to the oesophagus and to 20% of oesophageal volumes than those who were not affected. Wang’s study focussed on the association between oesophageal dosimetric parameters and the risk of grade ≥ 2 dysphagia and showed that maintaining the upper esophageal V25 at < 20% and V35 at < 0.27 mL may lower the risk [10]. Their findings provided further insights into the links between dosimetric parameters and risk of dysphagia, which were confirmed by present observations.
The limitations of the present study include the relatively small cohort, short follow-up, and its retrospective nature.
In conclusion, the efficacy and safety of HF were confirmed in real-life settings for unselected patients undergoing chest wall/breast and RNI. Present evidence supports the use of HF as standard treatment, providing patients with the advantages of shorter treatment times and reduced healthcare costs.
Footnotes
Conflict of interest: Authors declare no conflict of interests.
Funding: None declared.
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