Abstract
The aim of this investigation was to evaluate the feasibility of a shortened whole-breast irradiation schedule with a concomitant boost delivered to the tumor bed once-a-week in patients with early breast cancer submitted to conservative surgery. Patients and Methods: Patients with pT1 and pT2 M0 carcinoma of the breast were selected. The basic course consisted of 4600 cGy to the whole breast in 20 fractions, 4 times a week, for 5 weeks. Once a week, a concomitant boost of 120 cGy was delivered to the lumpectomy area. Results: From March 2007 to August 2008, we assessed this radiotherapy schedule in 377 patients. According to the RTOG/EORTC Toxicity Criteria, at treatment completion, 85% of patients showed G0-1, 12% G2 and 3% G3 skin toxicity. At 24 months, late toxicity was G0 in 92%, G1 in 7% and G2 in 1%; cosmesis was excellent or good in 95% of patients. To date, at a median follow-up of 33 months, no patient has yet experienced local relapse. Conclusion: A shortened whole-breast irradiation schedule with a weekly concomitant boost may be an alternative option with acceptable toxicity and excellent cosmesis.
Adjuvant radiotherapy (RT) has become the standard treatment for stage I-II breast cancer since ultimate locoregional control rates after conservative surgery and radiotherapy proved to be similar to those obtained by radical surgery alone (1, 2). Technical modalities of radiotherapy delivery include external 3-D conformal treatment, interstitial or endocavitary brachytherapy or intraoperative radiotherapy (3, 4). Traditionally, external RT consists of two planned courses: 50 Gy or an equivalent biological dose is delivered to the whole breast (WBI) in 25 fractions over 5 weeks (5 fractions per week) followed by 10-16 Gy delivered in 5-8 fractions over 1-2 weeks to the surgical site of tumor removal (3). In an attempt to intensify treatment especially when RT is delivered sequentially to chemotherapy several months after surgery a simultaneous boost has been introduced in clinical practice by using 3-D conformal radiotherapy or intensity-modulated RT (5,6). Preliminary results from experiences where a boost dose was delivered either daily after WBI (6) or weekly on Saturday as a sixth fraction (7) appear interesting, with a good feasibility in terms of acute toxicity. Since November 2004, we have proposed a concomitant boost technique delivered once a week (W-CB) during a moderately hypofractionated WBI course; compared to the daily-boost regimen (6) this W-CB schedule has practical advantages such as a very limited number of boost delivery sessions in an overall treatment time shortened to 5 weeks. Here we present the results in feasibility obtained at the University of Genoa, National Institute for Cancer Research, from 377 patients with early breast cancer treated with the W-CB schedule; the easy implementation of this RT schedule and relatively low incidence of acute and short-term late toxicity are presented and discussed in detail.
Patients and Methods
Patients. From March 2007 to August 2008, three hundred and seventy-seven consecutive female patients with early breast cancer scheduled to undergo adjuvant external RT after breast-conserving surgery were included in this controlled clinical trial. Eligibility criteria for enrollment were the following: breast carcinoma (ductal, lobular and other histotypes); stage pT1 or pT2, pN0-N3 without distant metastases (M0) according to UICC-TNM, 2002 version; exclusion criteria were: gross involvement of surgical margins; previous thoracic irradiation; synchronous second primary tumor; age greater than 80 years.
All the patients provided informed consent before starting RT. The RT schedule was planned either immediately after conservative surgery in patients at low-risk of distant failure or sequentially after chemotherapy in patients at high-risk of disease progression. The patients were assigned to different prognostic classes according to the St. Gallen Consensus Conference (8).
Radiotherapy fractionation. The basic course for WBI consisted of 4600 cGy prescribed to the ICRU 50 reference point dose and delivered in 20 fractions, 4 times a week, for 5 weeks. Once a week, immediately after WBI, a concomitant photon boost (W-CB) of 120 cGy was delivered to the lumpectomy area (Table I). The total nominal dose delivered to the tumor surgical bed (considering whole-breast dose and W-CB dose) was 52 Gy in 20 fractions over 5 weeks.
Radiobiological equivalent dose. Using the linear-quadratic cell survival model (9), we calculated the fraction size and total doses for the breast and boost volumes which were biologically equivalent to the total dose delivered in 2-Gy fractions with sequential boost. The biological comparison between the standard adjuvant RT schedule and explored W-CB schedule is shown in Table II. For this purpose, an α/β ratio of 4 Gy for tumor response, an α/β ratio of 10 Gy for acute responding normal tissues, an α/β ratio of 1.7 Gy for late (fibrosis) responding normal tissues and an α/β ratio of 2.5 Gy for vascular tissues were used.
Definition of target volumes and organs at-risk. A planning computed tomography (CT) scan was made for each patient. The patients were positioned on a wing-board with both arms raised above the head. Radiopaque catheters and markers were placed to locate palpable breast and surgical scars. An ink mark was made on the sternum skin to enable patient repositioning during treatment. Patients were scanned from the level of the larynx to the level of the upper abdomen, including both lungs, with a scan thickness and index of 5 mm. The CT data were transferred to the Eclipse Treatment Planning System (Varian, Palo Alto, CA, USA). The whole breast clinical target volume (WB-CTV) included the glandular breast tissue of the ipsilateral breast. The WB-CTV did not extend into the pectoralis major, nor the ribs, and did not include the skin. The whole-breast planning target volume (WB-PTV) was generated by adding a 3-D margin of 5 mm around the breast CTV. A margin of 10 mm was used in the cranial and caudal directions. The definition of the lumpectomy cavity was guided by the presence of surgical clips, as well as by hematoma, seroma and/or other surgery-induced changes considered to be part of the lumpectomy cavity. The CB-CTV was generated by adding a 3-D margin of 10 mm around the lumpectomy cavity. The CB-PTV was generated accordingly by adding a further margin of 5 mm. According to internal department policy, in patients with 4 or more positive nodes in the axilla, a supraclavicular field was added to cover areas at potential risk of microscopic disease in locoregional lymphatic areas: the hemi-field technique was used to match separation between the tangential and supraclavicular beams. The supraclavicular area was irradiated to the same prescription dose as the whole breast (46 Gy in 20 fractions over 5 weeks). Regarding organs at risk (OARs) the heart was contoured to the level of the pulmonary trunks superiorly, including the pericardium and excluding the major vessels. Both lungs were separately contoured, by considering only the ipsilateral lung as an OAR. The inner quadrants of the contra lateral breast were contoured as volume of interest (VOIs).
Treatment planning. Two opposing tangential beams were planned to conformally cover the WB-PTV. A multi-leaf collimator (MLC) was used to spare OARs according to individual anatomy. The appropriate gantry angles were determined in order to achieve maximal avoidance of the heart, ipsilateral lung and contralateral breast. Subsequently, a boost plan was created conformal to the CB-PTV. It consisted of two or more photon beams with manually selected gantry angles. Wedge and MLC shielding were selected in order to obtain a 95% isodose encompassing the boost PTV. A cumulative dose-volume histogram was created to evaluate dose distribution to WB-PTV, CB-PTV, OARs and VOIs and accept the proposed plan.
Radiation treatment. Generally the RT course started on Monday and ended on Friday. A weekly pause was planned for Wednesday. CB treatment was added each week on Thursday or on Friday. Radiotherapy was performed with 6-MV photon fields. Portal films of WBI and W-CB fields were taken at least once during the first treatment day and quantitatively compared to digitally reconstructed radiographs (DRR) and simulator images to ensure accurate set up.
Follow-up. Clinical evaluations were performed every two weeks during treatment course and at treatment completion. Follow-up evaluations was performed every six months after treatment end. Hormonal treatment, when indicated, was delivered during RT treatment and was not discontinued.
Evaluation of toxicity and cosmesis. Patients were evaluated in order to determine the severity and incidence of acute and late toxicity with the W-CB technique. Acute toxicity was assessed at RT completion and one month after a treatment course, whereas late toxicity was scored at least six months after the end of treatment. The maximal toxicity was scored using the Common Terminology Criteria (CTC) for Adverse Events, version 3.0 (10), using RTOG/EORTC scale for radiation-related toxicity as reference (11). This resulted in a toxicity score for each patient. Cosmesis was assessed 24 months after treatment end using a cosmetic scale of excellent, good, fair or poor as previously reported by Fowble et al. (12).
Results
Patients. At the time of the present report (September 2010), all 377 patients treated with the W-CB RT schedule had achieved the minimum follow-up of 24 months (median follow-up 33 months, range: 24-41 months). All the accrued patients were included in this analysis (by intention-to-treat). Patient characteristics are listed in Table II. A total of 182 (48%) patients received chemotherapy prior to adjuvant RT, and 294 (78%) patients received hormonotherapy concurrently to radiation. All patients completed the planned RT W-CB schedule. Fifteen patients who had four or more pathologically involved lymph nodes at axillary dissection underwent RT on breast and supraclavicular areas. To date, no patient has presented locoregional (breast, axilla and supraclavicular node area) recurrence; twelve patients presented distant disease progression at 18 (n=2), 25 (n=3), 27 (n=8), 28 (n=4) and 32 (n=3) months, respectively. As a consequence, 357 (94.6%) patients are alive and disease free.
Assessment of acute and 24-month late toxicity. Two clinical examinations were performed by a group of independent physicians at treatment completion and after 24 months. Locoregional side-effects were evaluated according to RTOG acute/late toxicity criteria (11). As shown in Table III, at the end of radiotherapy, among 377 evaluable patients, 85% showed G0-1, 12% G2 and 3% G3 skin toxicity. At 24 months, late skin and subcutaneous toxicity was assessed with score G0 in 92%, G1 in 7% and G2 in 1% of patients. Cosmesis was assessed and scored at 24 months after radiation completion: 85% of patients had excellent cosmesis, 10% good cosmesis and 5% had fair cosmesis. No patient showed poor cosmesis.
Discussion
In breast cancer management, recent advances have been focused toward the reduction of overall adjuvant RT treatment time (13, 14), by delivering a dose biologically equivalent to the standard schedule consisting of 6 weeks of treatment to a total dose up to 60 Gy. The rationale of delivering the boost dose to the surgical bed during WBI appears particularly appealing: the RT course may be shortened by one or two weeks and a greater dose per fraction is delivered to the area at high risk of residual microscopic disease. We designed an original fractionation schedule consisting of four treatment sessions per week over 5 weeks. The single daily fraction is 2.3 Gy and the total WBI dose is 46 Gy. To avoid a weekly radiation dose superior to 10 Gy, a planned treatment break is scheduled on Wednesdays (see Table I). Once a week, generally before the week-end break, a supplement of 1.2 Gy to the surgical tumor bed is simultaneously given with WBI: when the W-CB is delivered, the total dose delivered to the surgical bed is 3.5 Gy. This daily dose is below the threshold dose of 4 Gy that appeared to be correlated to an increased risk of severe late effects. As shown in Table IV, the nominal total dose administered with our schedule including WBI and W-CB techniques compares favorably with the standard fractionation dose adopted in breast irradiation (respectively, biologically effective dose (BED) for late response with an α/β=1.7 Gy: 134 Gy vs. 130 Gy, BED for acute response with an α/β= 10 Gy: 66 Gy vs. 72 Gy, BED for clonogen cancer cells response with an α/β= 4 Gy: 87 Gy vs. 90 Gy). As shown in Table IV, the two schedules are iso-effective with respect to vascular damage, while the W-CB schedule is less toxic (by 8.5%) than standard schedule regarding acute effects. In the comparison between the two regimens, although slightly less effective with respect to breast tumor control in the linear-quadratic model (by 4%), the biological dose of the W-CB regimen is not significantly different from the one estimated for the standard schedule. In the present report, according to recent investigations, we have assumed an α/β value of 4 Gy for tumor control which is close to that estimated for late responding tissues (15). If this were not the case, the use of an α/β=10 Gy (similar to that for squamous cell carcinoma) would result in a lower BED for tumor control with the W-CB schedule (by 8.5%).
The schedule was adopted for 377 consecutive patients who met the eligibility criteria. The clinical outcomes presented here clearly confirm the feasibility of this schedule in the treatment of patients submitted to RT after conservative surgery. Specifically, all the patients concluded their treatment in the planned overall time of 5 weeks. Twelve months after the end of radiotherapy, only three patients (1%) experienced G2 toxicity according to the RTOG/EORTC classification. Although 10 patients experienced G3 acute toxicity at the end of RT, no patient had G3 late toxicity after 24 months. In the 48 women with G2 toxicity at the last fraction of radiotherapy, local side-effects were not evident in the W-CB area but were frequently observed either in axillary area or in the lower border of the breast. Even if the assessment of cosmesis at 24 months may be considered only a surrogate end-point of long-term cosmesis, at that time an excellent or good score was reported for 85% of patients. To date, no patient has relapsed in the breast or locoregional lymph node areas. A longer follow-up is clearly needed to confirm that this schedule assures excellent locoregional disease control and very good cosmesis.
Conclusion
The proposed 3D conformal W-CB technique appears to be a straightforward technique that has the advantage of providing treatment flexibility, shortening the treatment course. We suggest that this radiation schedule may provide an alternative option to conventional WBI with acceptable acute and late toxicity, good compliance and excellent cosmesis.
- Received September 6, 2010.
- Revision received October 19, 2010.
- Accepted October 20, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved