Abstract
INTRODUCTION:
Postmastectomy radiotherapy reduces the risk of locoregional recurrence in breast cancer patients. The first results on accelerated radiotherapy in five fractions after breast conserving surgery are promising. The data on postmastectomy radiotherapy in five or six fractions is limited. We now present the data on acute and one-year toxicity and health related quality of life (HRQoL) after postmastectomy radiotherapy in patients of sixty years or older.
METHODOLOGY:
119 patients received five fractions of 5.7 Gy to the chest wall and five fractions of 5.4 Gy to the lymph nodes over ten to twelve days. Physician-assessed toxicity were scored using the Common Terminology Criteria for Adverse Events version 4.03 toxicity scoring system and the LENT-SOMA scale. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI-206). HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire the breast cancer specific module and the BREAST-Q questionnaire.
RESULTS:
Fatigue and edema were the most frequently observed physician-assessed toxicities. One year after radiotherapy only 12.9% experienced a clinically important deterioration in chest wall symptoms and in 22.9% of the patients were improved. Future perspective at one year after radiotherapy was improved in 40.0% of the patients. Patient-reported fatigue showed the greatest improvement.
CONCLUSION:
Accelerated radiotherapy should be considered to minimize the burden of breast cancer treatment, especially in older patients.
Introduction
Postmastectomy radiotherapy reduces the risk of locoregional recurrence in breast cancer patients, leading to an overall survival benefit in node-positive patients [1]. Greater benefits of postmastectomy radiotherapy are seen in patients with positive axillary nodes, large tumour size, involved margins and extensive lymphovascular invasion [2].
Earlier trials used a high number of fractions of radiotherapy spread out over several weeks. These extended schedules with up to twenty-eight hospital visits represent a substantial burden for the patient, especially for the elderly.
The first results on accelerated radiotherapy in five fractions after breast conserving surgery are promising: it appears to be as effective as schedules of fifteen or twenty-five fractions, with similar physician-assessed toxicity [3–5] and better HRQoL [6]. However, in a proportion of breast cancer patients, the extent of the tumour precludes breast conserving surgery and obligates mastectomy. The data on postmastectomy radiotherapy in five or six fractions is limited [7,8]. Ortholan et al. reported on 462 elderly patients treated with a six fractions schedule, one fraction a week. Only twenty percent of patients received a mastectomy [8]. They showed feasibility of this accelerated schedule with acceptable acute and late toxicity. Our research group previously published results of a 5 fractions schedule over twelve days in patients aged sixty-five years or older [7]. None of the twenty-three patients receiving chest wall irradiation developed grade 2 or higher acute dermatitis.
We now present the data on acute and one-year toxicity and health related quality of life (HRQoL) after postmastectomy radiotherapy in patients of sixty years or older.
Methodology
In the present analysis, a subset of 119 patients receiving postmastectomy radiotherapy in five fractions was selected from two prospective clinical trials investigating the feasibility of accelerated radiotherapy (NCT04098926 and NCT03121248 on www.clinicaltrials.gov). In both studies, patients were included aged 18 years or older treated with mastectomy, requiring adjuvant radiotherapy according to the multidisciplinary tumour board. Informed consent was obtained, signed and dated for all patients before specific protocol procedures. Exclusion criteria were distant metastases, bilateral breast irradiation, a history of radiation treatment to the same region, including radiation treatment to the contralateral breast, a life expectancy of less than 2 years, planned reconstructive surgery, conditions making toxicity evaluation difficult (e.g. skin disorders), inability to respect constraints on organs at risks and patients unlikely to comply with the protocol, e.g. unable to return for follow-up visits or unlikely to complete the study. Both trials were approved by the local ethics board of Ghent University Hospital. Patients were treated between January 2015 and April 2018 and received five fractions of 5.7 Gy to the chest wall and five fractions of 5.4 Gy to the lymph nodes. Treatment was delivered over ten to twelve days with patients never being treated on two consecutive days. Lymph node irradiation always included the level II–IV axillary nodes and if indicated, also level I. The parasternal nodes were never included in the target volume. A multi-beam intensity modulated radiotherapy technique was used for treatment delivery. In patients receiving chemotherapy preceding radiotherapy, at least a three-weeks interval between chemotherapy and radiotherapy was respected. Endocrine therapy was allowed concomitantly with postmastectomy radiotherapy.
Physician-assessed toxicity and HRQoL were scored at baseline, and two to four weeks and one year after radiotherapy. Physician-assessed acute toxicity was scored using the Common Terminology Criteria for Adverse Events version 4.03 toxicity scoring system and one-year toxicity using the LENT-SOMA scale. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI-206). A difference of at least one grade between baseline and the subsequent measuring points was considered a deterioration in toxicity. HRQoL was assessed using specific domains of the European Organisation for Research and Treatment of Cancer (EORTC) 30-item Quality of Life Questionnaire (QLQ-C30), the breast cancer specific module of the EORTC QLQ (QLQ-BR23) and the BREAST-Q questionnaire. Significant differences in HRQoL between two to four weeks and baseline were tested with the Wilcoxon matched-pairs signed ranked test and between one year and baseline with the Mann-Whitney U test, while not for all patients one-year results were available yet. Bonferroni-correction for multiple testing lead to a p-value for significance of <0.006. Based on EORTC guidelines, a difference of more than ten points was considered as an improvement or a deterioration in HRQoL.
Health related quality of life scores (mean ± SD)
Health related quality of life scores (mean ± SD)
SD = Standard deviation; aWilcoxon matched-pairs signed-ranks test; bMann-Whitney U test; cHigher score indicates better functioning; dHigher score indicates more symptoms; *Significant after Bonferroni correction.
Data is known for 119 patients at baseline and two to four weeks after radiotherapy, and at one year for 70 patients. Patients are between 61 and 85 years old (mean 71.3). Less than half of them (44.5%) received chemotherapy. More than half of the patients received endocrine therapy: 21.8% tamofixen and 34.5% an aromatase inhibitor. The statistical analysis (Table 1) of the HRQoL scores at baseline, two to four weeks and one year after radiotherapy only shows a significant difference for future perspective with patients having a significantly better perspective one year after radiotherapy (61.1 versus 72.1, p = 0.003). Chest wall symptoms are also more pronounced two to four weeks after radiotherapy, although only borderline statistically significant (15.6 versus 19.7, p = 0.007).
In Table 2, the number of patients experiencing toxicity (in grades) and a deterioration in physician-assessed toxicity compared to the baseline, and in Table 3 a deterioration or improvement of HRQoL are listed. Fatigue and chest wall edema were the most frequently observed physician-assessed toxicities. Patient-reported chest wall symptoms increased in a quarter of the patients two to four weeks after radiotherapy. However, one year after radiotherapy only 12.9% experienced a clinically important deterioration in chest wall symptoms and in 22.9% of the patient’s chest wall symptoms were improved compared to baseline. Future perspective at one year after radiotherapy was improved in 40.0% of the patients. Patient-reported fatigue showed the greatest improvement shortly after postmastectomy radiotherapy. However, in the same percentage it was more pronounced. One year after radiotherapy, a quarter of the patients still reported a deterioration in fatigue; fortunately half of the patients experienced less fatigue at that time point. One year after treatment, many patients also experienced a worsening of physical functioning (31.4%). In 17.1% of the patients physical functioning had improved.
Physician-assessed toxicity
Physician-assessed toxicity
Changes in health-related quality of life
Radiotherapy leads to acute skin toxicity, late side effects and has an impact on HRQoL [1]. Long treatment duration and a high number of hospital visits may also be a burden, certainly for older patients. Accelerated radiotherapy schedules in five fractions should certainly be considered in this patient group, since recent randomized trials show their efficacy and safety after breast conserving surgery [3,4]. However, data on postmastectomy radiotherapy in five fractions remained scarce.
Acute toxicity was measured at the end of radiotherapy and 2 to 4 weeks after irradiation. In earlier studies of irradiation in 5 fractions after breast conserving surgery, most toxicity did not seem to aggravate beyond 2 weeks after radiotherapy, except for some very rare grade 3 toxicity, appearing at 4 weeks after radiotherapy, possibly explained by the use of a sequential boost which is not the case in mastectomy irradiation. Our data show that the frequency of toxicity was lower at the last follow-up visit than at the end of radiotherapy, suggesting that maximum toxicity occurred earlier than 2 weeks after RT. Patients were also asked to contact us in case toxicity got worse after the last follow-up visit.
Comparison of our physician-assessed toxicity rates to other reports on postmastectomy radiotherapy is difficult. In the publication of Ortholan et al. 74% of patients developed acute dermatitis with the 6 fractions schedule [8]. Our schedule of 5 fractions seems to be milder with only twenty-one percent of patients developing dermatitis at two to four weeks after radiotherapy. However, eighty percent of patients in the study of Ortholan et al. were treated after breast conserving surgery. In this study thirty percent of patients developed chronic skin changes or fibrosis, which is comparable to our results for colour changes and fibrosis at one year. In another publication on postmastectomy radiotherapy with more extended radiotherapy schedules of sixteen to twenty-five fractions, the authors observed a forty to sixty percent of skin and subcutaneous tissue disorders [9]. In our cohort, fatigue, pain, chest wall edema and dermatitis were seen the most during and shortly after radiotherapy. Physician assessed fatigue and chest wall edema became worse one year later, but pain significantly improved one year after radiotherapy, compared to shortly after radiotherapy.
Half of the patients still experience a deterioration in physician-assessed fatigue one year after treatment, while this is only twenty-five percent when assessed with the HRQoL questionnaires. However, almost half of patients improved for patient-reported fatigue one year after radiotherapy. In physician-assessed fatigue only being tired is taken in account and every deterioration in score was taken into account. The score of patient-related fatigue is based on different items: being tired, feeling weak and needing to rest at day and a difference in score was only reported as a deterioration in case the difference was at least ten points as proposed by the EORTC. The high incidence of fatigue at one year after irradiation is probably not only radiotherapy-related, but could be an effect of chemotherapy (44.5% of patients) and/or endocrine therapy (56.3% of patients).
We only observed a significant difference in HRQoL scores between baseline and one year after radiotherapy for future perspective with patients having a significantly better future perspective at one year. When looking at individual patients for the different HRQoL items, some patients experience an improvement in HRQoL at one year and some experience a deterioration. However, these changes over time cannot solely be attributed to radiotherapy as shown by Velikova et al., who investigated the HRQoL after postmastectomy radiotherapy in fifteen to twenty-five fractions [10]. Aside from chest wall symptoms, they saw few differences in HRQoL between patients receiving postmastectomy radiotherapy and patients receiving mastectomy without radiotherapy. The mean scores of social functioning, global health status chest wall symptoms and physical functioning were comparable to ours at one year after radiotherapy. However, for global health status and social functioning, we did not observe a difference between baseline and one year, while the population of Velikova had lower baseline scores which had improved at one year after radiotherapy. For fatigue, both baseline scores and scores at one year were higher in our population. Compared to Velikova et al. our patients experienced less pain and arm symptoms and better future perspective.
While less acute toxicity may be expected in an accelerated irradiation schedule, the opposite might be faired for late toxicity. The FAST and FAST-FORWARD trials did not see more late toxicity, respectively at 10 and 5 years. Also, for the schedule of 5 fractions over 10–12 days in patients after breast conserving surgery, less toxicity was seen 2 years after irradiation, except for fibrosis outside the tumour bed, which was caused by the simultaneous integrated boost.
Previous work from our group showed that one year after breast conserving surgery and radiotherapy, patients treated with the accelerated schedule in five fractions show more improvement and less deterioration of HRQoL than patients treated with a fifteen-fractions schedule [6]. Although this is a small single-center trial with only limited follow-up, our data add to the scarce evidence that radiotherapy in five fractions to the chest wall and lymph nodes is safe, with comparable toxicity and HRQoL as in normofractionation and hypofractionation schedules. Therefore, accelerated radiotherapy should be considered to minimize the burden of breast cancer treatment, especially in older patients.
Footnotes
5.
During the conduct of this work, Liv Veldeman was recipient of a Clinical Mandate of Stand up to Cancer (Flemish Cancer Society). This work was funded by the Foundation for Scientific Research Flanders (FWO.OPR.2016.0078.01) and Stand up to Cancer (Flemish Cancer Society). None of the other auteurs have a conflict of interest.
Author contributions
Vincent Vakaet: conception and design, data analysis, statistical analysis, writing of manuscript
Hans Van Hulle: data analysis, statistical analysis, writing of manuscript
Viktor Quataert: data analysis, statistical analysis, writing of manuscript
Pieter Deseyne: patient accrual, review of manuscript
Max Schoepen: technical device, review of manuscript
Leen Paelinck: data analysis, review of manuscript
Giselle Post: patient follow-up, data collection, review of manuscript
Annick Van Greveling: patient follow-up, data collection, review of manuscript
Bruno Speleers: treatment planning, review of manuscript
Marc Mareel: patient accrual, review of manuscript
Wilfried De Neve: patient accrual, review of manuscript
Chris Monten: patient accrual, review of manuscript
Liv Veldeman: study coordination, patient accrual, data analysis, revision of manuscript
All authors read and approved the final manuscript.