|Ahead of print
Assessment of toxicities and outcomes in patients with breast cancer treated with hypofractionated radiotherapy
M Sindhu, Monica Malik, Syed F Ahmed, Deepthi Valiyaveettil
Department of Radiation Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
|Date of Submission||13-Oct-2018|
|Date of Decision||31-Mar-2019|
|Date of Acceptance||16-Apr-2019|
|Date of Web Publication||05-Aug-2020|
Department of Radiation Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
Background: Hypofractionation is now becoming the standard of care in breast irradiation. The aim of this study was to assess the toxicities and outcomes in patients with breast cancer treated with hypofractionated radiotherapy (HFRT).
Methods: Patients with localized breast cancer who received adjuvant HFRT between 2013 and 2015 with a minimum follow-up of 6 months following radiation were included in this prospective study. Late toxicities were assessed using CTCAE v 4 and included chest/breast pain, limb pain, limb edema, skin pigmentation, skin fibrosis, and shoulder movement restriction. Outcomes assessed included locoregional control, disease-free survival, and overall survival. Statistical analysis was done using Microsoft Excel and SPSS v22.
Results: A total of 81 patients fulfilled the inclusion criteria, of which 19 patients had died during follow-up. Regional nodal irradiation was done in 63 (77.8%) patients using the same hypofractionated schedule of 40 Gy in 15 fractions. Late toxicities were assessed for 62 patients. The median follow-up following the course of hypofractionated radiation was 45 months (range 14 - 65 months). Late toxicities were assessed for 62 patients. Grade 1/2 chest/breast pain, limb pain, limb edema, skin pigmentation, skin fibrosis, and shoulder movement restriction were seen in 11%, 12%, 7%, 6%, 8%, and 11% of cases, respectively. Distant recurrences were seen in 8% of cases, and there were no locoregional recurrences. Five-year overall survival was 76.5%.
Conclusion: HFRT to whole breast or chest wall and the regional nodal areas was well-tolerated with acceptable rates of late toxicities on follow-up.
Keywords: Breast cancer, hypofractionation, late toxicities
|How to cite this URL:|
Sindhu M, Malik M, Ahmed SF, Valiyaveettil D. Assessment of toxicities and outcomes in patients with breast cancer treated with hypofractionated radiotherapy. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 1]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=291415
| » Introduction|| |
Breast cancer is the second most common cancer in the world with over two million cases diagnosed in 2018. According to GLOBOCAN 2018, it is the most common cancer in women, accounting for 24.2% of all cancers in women. Management of breast cancer has a multimodality approach, and adjuvant RT plays a vital role in many patients.
There is clinical evidence that breast tumors have an intermediate α/β ratio, which is a standard parameter to define the cell survival in radiation therapy, unlike most tumors which have high α/β ratio. As the linear quadratic model describes tissues with low to intermediate α/β ratio more sensitive to high-dose per fractionation, there has been a growing trend toward hypofractionation, which involves delivering a higher dose per fraction for a smaller number of fractions for a higher biologically equivalent dose. Increased dose per fraction increases tumor kill, but relative higher dose to late-responding tissues raises concerns about late-tissue toxicity. Most hypofractionation trials reported till date have included patients with early breast cancer post breast conservation surgery (BCS), most of whom did not receive chemotherapy with very few patients receiving regional nodal irradiation,, (RNI). Given the encouraging results of hypofractionated radiotherapy (HFRT) in these patients, we prospectively used this strategy in patients with locally advanced breast cancer (LABC) who underwent BCS/modified radical mastectomy (MRM) and RNI. There are sparse data on the role, toxicity, and outcomes of HFRT in this subset of patients. The aim of this study was to assess the late toxicities and outcomes in patients with breast cancer treated with HFRT.
| » Materials and Methods|| |
Patients with localized breast cancer who received adjuvant HFRT to whole breast or chest wall between 2013 and 2015 were invited for this prospective study. All study patients were required to have at least 6 months of follow-up, following completion of HFRT. Patients underwent BCS or mastectomy and could have received chemotherapy, hormonal therapy, and anti-HER-2 therapy as indicated. All adult female patients with breast cancer who received HFRT as a part of curative treatment were eligible. Patients with recurrent or metastatic disease were excluded. Informed consent and institutional review board approval were taken. Demographic data, disease-related, and treatment-related data were collected retrospectively from patient records. Late toxicities were assessed using CTCAE v4. Parameters assessed for late toxicity included chest/breast pain, limb pain, limb edema, skin pigmentation, skin fibrosis, and shoulder movement restriction. Dosimetric data including V10, V15, and V20 of lung and mean heart dose were collected from treatment planning system. Survival analysis was done using Kaplan–Meier estimates using IBM SPSS version 22 software (IBM Corp., Armonk, NY, USA). Institutional review board permission was taken for this study.
| » Results|| |
A total of 81 patients were eligible for the study. At a median follow-up of 45 months (range 14 - 65 months), 19 (23.4%) patients had died. In all, 62 patients consented for evaluation and were assessed for late toxicities using CTCAE v4.
Patient characteristics are summarized in [Table 1]. Two patients (2.4%) were medically inoperable and underwent lumpectomy alone under local anesthesia. A total of 25 (30%) patients underwent BCS and 54 (67%) patients underwent MRM. Histopathology details are summarized in [Table 2].
Seven patients received neoadjuvant chemotherapy and the rest received anthracycline-based adjuvant chemotherapy. Four patients did not receive chemotherapy due to cardiac comorbidities. All patients received hypofractionated RT to a total dose of 40 Gy in 15 fractions to whole breast or chest wall with three-dimensional conformal radiotherapy (3DCRT). Tumor bed boost was given to the patients who underwent BCS with a dose of 10 Gy over five fractions. RNI was done in 63 (77.8%) patients using the same hypofractionated schedule of 40 Gy in 15 fractions. All patients completed the planned course of radiation without any significant interruptions. In all, 53 (65%) patients received adjuvant endocrine therapy and 7 (9%) patients received trastuzumab. Dosimetry details are given in [Table 3].
Late toxicities were recorded at a median follow-up of 45 months. Dyspnea of grade I was seen in three patients (4.8%). Grade 1/2 late toxicities, namely, chest/breast pain, limb pain, limb edema, skin pigmentation, subcutaneous fibrosis, and shoulder movement restriction were seen in 11%, 12%, 7%, 6%, 8%, and 11% of cases, respectively. None of the patients had grade 3/4 toxicities.
At a median follow-up of 45 months, 19 (23.4%) patients had died. Seven (8.6%) patients died due to distant recurrence with bone, brain, and lung metastases in 3 (3.7%), 2 (2.4%), and 2 (2.4) patients, respectively. One patient died due to febrile neutropenic sepsis during salvage chemotherapy. Twelve patients died at home and the cause of death could not be ascertained. None of the patients had locoregional recurrence. Three- and 5-year overall survival was 79% and 76.5%, respectively [Figure 1] and [Figure 2].
| » Discussion|| |
This study reflects the clinical experience of patients with breast cancer treated with HFRT post-BCS or MRM over a period of 3 years. Most studies have evaluated the role of HFRT only in patients with early breast cancer. In our study, we have also included patients with LABC, most of whom also received HFRT for RNI.
Cardiac toxicity is a major concern in patients with breast cancer. Radiotherapy, systemic chemotherapy, hormonal therapy, and targeted therapy all contribute to cardiac hazard.,,,,, The breast cancer RT techniques used in the past delivered high cardiac doses that increased the risk of cardiac mortality and morbidity which was significantly observed in patients with left-sided breast cancer. With the advancement in radiation techniques, 3DCRT, intensity-modulated radiation therapy, and tangential fields tend to deliver lower cardiac doses., Also, using dose–volume histograms the dose received to volume of heart can be minimized accordingly. Taylor et al. showed that the mean left heart dose was 0.9–14.0 Gy for tangential fields on breast or chest wall with commonly used RT regimens. Darby et al. concluded that women who received a heart dose >5 Gy had increased heart disease risk. We found the mean dose to heart was 5.2 Gy (range 1.4 Gy–14.7 Gy) in patients with left-sided breast cancer. In our institute, the heart dose is minimized using multi-leaf collimators (MLCs) and field-in-field technique. So even with hypofractionation, where dose per fractionation is more than 2 Gy, the mean heart dose appears to be acceptable. However, long-term follow-up is needed to assess the impact of cardiac radiation doses.
Radiation-induced lung injury manifests either early (radiation pneumonitis) or late (lung fibrosis)., V20 and V30 predict the incidence and severity of radiation-induced lung toxicity. The optimal threshold of V20 for local regional irradiation and for simple local irradiation is 39.8% and 20.2%, respectively, in conventional fractionation.,, As we used hypofractionation, V10 and V15 were also assessed in addition to V20. We have found that in the lung V10, V15, and V20 were 35.7%, 32.6%, and 31.2%, respectively, which shows the volume of lung irradiated was acceptable in our study population where 77.8% of patients had RNI.
At 3 years' follow-up, Whelan et al. found grade 1 and grade 2/3 skin toxicities in 39% and 5%, respectively, and grade 1 and grade 2/3 subcutaneous fibrosis in 8% and 2.2%, respectively, which was comparable to our study (subcutaneous fibrosis grades 1 and 2 was seen in 8% after a median follow-up of 45 months). Grade 1/2 skin toxicities were seen only in 6% of patients. No grade 3 and 4 late toxicities were seen in our study. In the past, breast cancer–associated lymphoedema (BCAL) was one of the significant reasons of functional and psychological morbidity in breast cancer survivors. With improved surgical techniques and RT delivery techniques, the incidence of BCAL decreased.,, In our study, we have measured the circumference of ipsilateral and contralateral arms at two points, 10 cm above the olecranon process and 5 cm below the olecranon process. In Standardisation of Breast Radiotherapy (START) trials, only a small portion of patients received lymphatic radiotherapy. Most of the patients in our study received RNI and only three patients (7.5%) had 1–1.5 cm increase in ipsilateral arm circumference when compared with contralateral arm. This shows hypofractionation regimens can be safer even to the regional nodes. With the advancement in RT delivery and techniques, the incidence of toxicities has decreased, but it can still affect patients' quality of life.
In a study by Whelan et al., the 5-year local recurrence-free survival was 97.2%. In our study, there were no local regional recurrences after a median follow-up of 45 months, whereas distant recurrence was 8.6%. Three- and 5-year overall survival was 79% and 76.5%, respectively.
Limitations of the study
Late toxicities and recurrences can continue to occur in patients with breast cancer even after 15–20 years of follow up. Hence, the study duration is relatively short. Long-term follow-up data are awaited.
| » Conclusion|| |
Hypofractionated radiation to whole breast or chest wall and regional nodes was well-tolerated with low and acceptable rates of late toxicities in patients with LABC. There were no locoregional recurrences. Survival outcomes were similar to those reported in literature. Our results suggest that HFRT can be offered to patients with LABC who are planned for locoregional irradiation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]