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Abstract
Introduction Shortening the duration of postoperative radiotherapy (RT) for breast cancer while maintaining efficacy and safety has become a significant trend. The 3-week regimen of 40–42.5 Gy in 15–16 fractions is now a preferred option in clinical practice. Following the publication of the 5-year outcomes from the Fast-Forward trial, interest in 1-week regimens has surged, prompting the initiation of multiple studies. However, trials exploring the 1-week regimen for regional nodal irradiation (RNI), especially involving internal mammary nodes (IMN), remain scarce. Additionally, the optimal fractionation scheme for tumour bed boost in the era of ultra-hypofractionated regimens is still debated. To address these gaps, we initiated the adjuvant regional nodal radiation therapy for one week in breast cancer (ARROW) trial to evaluate the feasibility of a 1-week regimen for RNI of 26 Gy in five fractions, with optional sequential tumour bed boost of 10.4 Gy in two fractions. The findings from our trial are expected to extend the application of ultra-hypofractionated regimens to include sequential tumour bed boosts and RNI, pioneering its use in IMN irradiation.
Methods and analysis The ARROW trial is an open-label, single-arm, multicentre phase II trial, encompassing four teaching hospitals in China. Enrolled patients will receive a total of 26 Gy in five fractions to ipsilateral whole breast/chest wall and regional regions, including supraclavicular/infraclavicular nodes, IMN and any portion of the undissected axilla deemed at risk. A sequential tumour bed boost of 10.4 Gy in two fractions is delivered in patients at high risk for recurrence, which is at the discretion of the radiation oncologist. The sample size for the ARROW trial was 197 patients. Both intensity-modulated radiation therapy and proton therapy are permitted. The primary endpoint is acute radiation-induced toxicity, graded according to Radiation Therapy Oncology Group (RTOG) criteria and CTCAE V.3.0. Secondary endpoints include cosmetic outcomes for breast-conserving surgery, late radiation-induced toxicity, local regional recurrence, distant metastasis, invasive tumour-free survival, overall survival and quality-of-life assessment.
Ethics and dissemination The trial has been approved by the Ethical Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, as well as approvals from the ethical committees of each participating centre have also been obtained. Research findings will be submitted for publication in peer-reviewed journals.
Trial registration number ARROW trial: NCT04509648.
- Breast tumours
- RADIOTHERAPY
- Radiation oncology
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The ARROW trial evaluates the feasibility of a 1-week regimen for regional nodal irradiation of 26 Gy in five fractions in China.
A sequential tumour bed boost of 10.4 Gy in two fractions is used in the trial.
Both intensity-modulated radiation therapy and proton therapy are permitted.
One of the limitations is that this study does not stratify according to clinicopathological, subtype or gene information.
Another limitation is that this trial is a single-arm phase II study; however, it could provide the safety profile of the ultra-hypofractionated regimen in tumour bed boost and internal mammary nodal irradiation, serving as a foundation for initiating a subsequent phase III randomised controlled trial of 1-week regimen.
Background
Breast cancer is the most prevalent malignant tumour among women.1 Postoperative radiotherapy (RT) can significantly reduce recurrence risk and improve survival for patients undergoing breast-conserving surgery (BCS) or those at high risk post-mastectomy.2–6 However, the traditional 5–7-week RT regimen may reduce patient compliance and strain limited RT resources. The UK START trials identified an α/β value of approximately 3.5 Gy for breast cancer tissue, indicating that hypofractionated (HF) RT, with higher single-fraction doses, is more suitable for breast cancer.7
In recent years, evidence from randomised trials and real-world studies has established the 3-week regimen of 40–42.5 Gy in 15–16 fractions as the preferred option for whole breast irradiation (WBI).7–13 This practice has gradually expanded to include regional nodal irradiation (RNI).14–17 In a randomised trial with a median follow-up of 58.5 months, Wang et al15 demonstrated that HF-RNI of 43.5 Gy with 2.67 Gy per fraction was non-inferior to the 5-week regimen of 50 Gy with 2 Gy per fraction for locoregional control and adverse effects.
The Fast-Forward trial marked a pivotal advancement by condensing the RT regimen to 1 week for WBI using ultra-hypofractionation.18 With a median follow-up of 71.5 months, this trial demonstrated that a 1-week regimen of 26 Gy in 5 fractions was non-inferior in local control and normal tissue effects compared with the standard 3-week regimen of 40 Gy in 15 fractions. However, this trial gave the tumour bed boost using conventional fraction, extending the overall RT duration to 2 or 2.5 weeks. The feasibility of ultra-hypofractionation in the tumour bed boost irradiation remains unknown. The Nodal Sub-Study of the Fast-Forward trial further explored the non-inferiority of the 1-week regimen of RNI in patient-reported arm/hand swelling.19 This study excluded patients with an indication of internal mammary nodal irradiation (IMNI) due to the perceived uncertainty of its value at the time of protocol design. With advancements in RT technology, there has been a significant reduction in heart and lung doses associated with IMNI, leading to increasing recognition of its benefits in recent years.2 4–6 20 21 However, limited data are available on the use of a 1-week regimen in IMNI.
To fill in these gaps, we initiated the ARROW trial to evaluate the feasibility of a 1-week regimen for RNI of 26 Gy in five fractions for early breast cancer, with optional sequential tumour bed boost of 10.4 Gy in two fractions. The results from our trial are expected to confirm the feasibility of a 1-week regimen and extend the use of ultra-hypofractionated regimens to include sequential tumour bed boosts and RNI, pioneering its application in IMNI.
Methods
Study design
The ARROW trial is an open-label, single-arm, multicentre phase II trial being conducted at four teaching hospitals in China. The primary objective is to assess the feasibility of a 1-week regimen of 26 Gy in five fractions for patients with early breast cancer. Both intensity-modulated radiation therapy (IMRT) and proton therapy are permitted. The primary endpoint is the incidence of grade≥2 acute radiation-induced toxicities at any time from the start of RT to 6 months after completion. Secondary endpoints include cosmetic outcomes for patients with BCS, late radiation-induced toxicity, local regional recurrence, distant metastasis, invasive tumour-free survival, overall survival (OS) and quality of life. The radiation-induced toxicity was graded using RTOG criteria and CTCAE V.3.0.
In the ARROW trial, participants receive 26 Gy in five fractions for the ipsilateral whole breast or chest wall (detailed in online supplemental table S1) and regional lymphatic regions, including supraclavicular and internal mammary nodes, and any portion of the undissected axilla deemed at risk (detailed in online supplemental table S2). A sequential tumour bed boost of 10.4 Gy in two fractions is delivered in patients at high risk for recurrence, which is at the discretion of the radiation oncologist. Figure 1 illustrates the study design of the trial. The ARROW trial (NCT04509648) is registered on ClinicalTrials.gov.
Supplemental material
Study design. Fx, fractions.
Participants and recruitment
The clinical team will identify and approach eligible patients during their initial visit to the Department of Radiation Oncology, offering the opportunity for potential study participation. They are provided with a comprehensive overview of the study’s objectives, procedures, benefits and risks to thoroughly understand their involvement. Those who express interest, meet the inclusion criteria and fully comprehend the study’s implications will be invited to provide written informed consent. Following voluntary consent, participants will be officially enrolled in the study.
The first patient of the ARROW trial was enrolled on 21 January 2021 and is expected to complete enrolment by December 2025.
Inclusion and exclusion criteria
Inclusion
Aged>18 years old.
Pathologically invasive breast cancer.
Undergoing BCS or mastectomy with reconstruction allowed, along with axillary lymph node dissection (ALND) or sentinel lymph node (SLN) biopsy.
Axillary lymph node metastasis confirmed histologically (involving one or more nodes) or node-negative axilla with an indication for RNI as determined by the radiation oncologist.
Karnofsky Performance Status scoring≥80, and anticipative OS>5 years.
Surgery wound healed without infection.
Negative pathologically surgical margin.
Oestrogen receptor, progesterone receptor, HER-2 and Ki67 index assessment on the primary breast tumour or axillary nodes is feasible.
Women of childbearing potential must agree to use adequate contraception for up to 1 month before study treatment and the duration of study participation.
Ability to understand and willingness to participate in the research and sign the consent forms.
Exclusion
Pathologically positive ipsilateral supraclavicular lymph node.
Pathologically or radiologically confirmed involvement of ipsilateral internal mammary lymph nodes.
Pregnant or lactating women.
Severe non-neoplastic medical comorbidities that preclude radiation treatment (eg, severe ischaemic heart disease, arrhythmia, chronic obstructive pulmonary disease).
History of non-breast malignancy within 5 years with the exception of lobular carcinoma in situ, basal cell carcinoma of the skin, carcinoma in situ of skin, adenocarcinoma in situ of the lung and carcinoma in situ of the cervix.
Simultaneous contralateral breast cancer or a history of ipsilateral breast cancer (including ductal carcinoma in situ (DCIS)).
Previous RT to the neck, chest and/or ipsilateral axillary region.
Active collagen vascular disease.
Definitive pathological or radiological evidence of distant metastatic disease.
Primary T4 tumour.
Radiotherapy
General consideration
Both IMRT and proton therapy are allowed. The main goal is to ensure that the prescribed dose covers the planning target volume (PTV) in IMRT and clinical tumor volume (CTV) in proton therapy while minimising the radiation dose to organs-at-risk (OARs). Proton therapy is prioritised for left-sided IMNI, patients at high risk of radiation-induced toxicities or cases where heart or lung dose constraints cannot be achieved with IMRT. In centres without proton facilities, IMRT is used as the standard approach. RT should start within 12 weeks after the last date of surgery or 8 weeks after the final dose of planned adjuvant chemotherapy. Planned adjuvant endocrine therapy, immune checkpoint inhibitor and anti-HER-2 therapy are allowed to continue during RT.
Patient positioning and immobilisation
Patients are positioned supine with arms abducted to at least 90°. The immobilisation methods are tailored to each centre’s standards, prioritising position stability and repeatability throughout RT to ensure consistent dose delivery. Thermoplastic masks are recommended for head immobilisation.
The CT-based treatment planning with scan thickness of 3–5 mm should start at the level of the cranial base and extend to at least 4 cm below the ipsilateral or contralateral inframammary fold. Radiopaque markers are used to delineate the surgical scar and breast contour.
When using a proton therapy system with only two-dimensional image guidance, it is recommended to place non-radiopaque metal spheres next to the target volume. These spheres will serve as a reference for position during image registration and should be removed before treatment.
Volumes of interest
The target volumes include ipsilateral whole breast or chest wall and regional lymphatic regions, including supraclavicular/infraclavicular nodes, internal mammary nodes and any portion of the undissected axilla deemed at risk. An exhaustive atlas detailing these target volumes is provided in online supplemental appendix, tables S1–S3.
The margins between PTV and CTV depend on the institutional standards of each study centre with a general recommendation of 5–8 mm. OARs, including the heart, bilateral lungs, contralateral breast, spinal cord, ipsilateral humeral head and ipsilateral brachial plexus, were contoured based on RTOG guidelines. A ‘skin ring’ should be contoured to evaluate skin doses in proton therapy. For patients undergoing BCS, this ring is defined as a 3 mm deep tissue layer, while for mastectomy patients, it is a 5 mm deep layer from the external body surface.
Prescription and normal tissue constraints
The regimen of 26 Gy in 5 fractions has been confirmed non-inferior in efficacy and safety to the standard 40 Gy in 15 fractions, as evidenced in the Fast-Forward trial and its nodal substudy.7 18 Thus, for all enrolled patients, the prescribed dose to the ipsilateral whole breast or chest wall and regional lymph region is 2600 cGy in five fractions, one time per day over 1 week. A sequential tumour bed boost of 1040 cGy in two fractions one time per day is delivered in patients at high risk for recurrence, which is at the discretion of the radiation oncologist.
The specific dose requirements for the PTV in IMRT, the CTV in the proton therapy and dose–volume constraints for OARs are outlined in online supplemental appendix, tables S4 and S5.
Treatment planning
Patients undergoing photon therapy are treated with an IMRT technique using 6 MV X-rays, as described in the published literature.22 A 3–5 mm skin bolus is allowed for chest wall irradiation.
For proton therapy, a relative biological effectiveness coefficient of 1.1 is applied. Pencil beam scanning (PBS) proton therapy is recommended, with passive scattering proton therapy allowed. When using passive scattering, it is best to use at least two fields to reduce skin dose. In PBS proton therapy, range shifters can be used to improve dose coverage for superficial target regions. Radiopaque markers on the patient’s surface, including the ball bearing for isocenter localisation and the wire marking the scar, were contoured and assigned a stopping power ratio (SPR) matching that of air to ensure accurate dose calculations. For the surgical clip within the tumour bed, the SPR was set according to material-specific values from the product brochure. Plan robustness, the capacity of a proton plan to maintain its objectives amidst uncertainties, is essential and should be assessed for each patient’s treatment plan. Setup uncertainties are kept within ±3 mm for positioning and ±3.5% for range.
Treatment verification schedule and quality assurance
For the first five patients at each participating centre, a senior radiation oncologist must review and approve the contouring and dose–volume constraints for CTV and OARs. Any deviations from the specified protocol requirements must be documented and should not exceed 10% of enrolled patients.
Before each treatment session, verify patient positioning using an electronic portal imaging device, cone-beam CT (CBCT) or other available image-guided radiation therapy techniques to ensure any three-dimensional positional discrepancies are <3 mm. If 2D imaging is used in the proton therapy system, non-radiopaque metal spheres are recommended to serve as fiducials for image registration, but these should be removed before treatment.
Criteria for discontinuing interventions
Patients can withdraw from the trial at any time without penalty. If they withdraw before starting RT, they will receive standard care according to institutional guidelines. The date of withdrawal will be recorded as the day the study team acknowledges the notification. For patients who experience adverse events (AEs), the decision to continue or discontinue RT rests with the principal investigator (PI) or designated medical officer at the participating centre, which will be based on an assessment of the event’s severity and its potential impact on the patient’s health and safety. All AEs will be documented in the electronic Case Report Form (eCRF) and reported on time. Continued monitoring will be conducted post-withdrawal to ensure safety and proper care. The informed consent form provides details on the criteria for stopping an intervention or withdrawing from the trial.
Endpoints
Primary endpoint
Acute radiation-induced toxicities: the incidence of grade≥2 acute toxicities at any time from the start of RT to 6 months after completion.
Secondary endpoints
Late radiation-induced toxicities: the incidence of late toxicities at any time from 6 months to 5 years after the completion of RT, accessed according to RTOG criteria and CTCAE V.3.0.
Cosmetic outcomes: for patients undergoing BCS, cosmetic results are evaluated using the Harvard Breast Cosmesis Scale, ranging from excellent (minimal or no difference compared with the untreated breast), good (slight difference in the size or shape), fair (obvious difference in the size or shape) to poor (marked change in size or shape).
Local regional recurrence: the first recurrence in the ipsilateral breast, chest wall or regional nodes (ipsilateral axillary, supraclavicular or internal mammary nodes) confirmed by histology or cytology.
Distant metastasis-free survival (DMFS): time from enrolment to the occurrence of distant tumour recurrence, or until the last follow-up.
Invasive recurrence-free survival (IRFS): time from enrolment to the occurrence of invasive tumour recurrence, distant metastases or until the last follow-up, including second invasive primaries of the breast.
OS: time from enrolment to death from any cause or until the last follow-up.
Exploratory endpoints of the trial are quality of life using self-administered questionnaires EORTC QLQ-C30 and QLQ-BR23 (Chinese version).
Outcome measures and follow-up
The schedule of enrolment, interventions and assessments is detailed in table 1. Any radiation-induced toxicities, tumour recurrence events and deaths must be thoroughly documented in the eCRF. The radiation-induced toxicities are graded using RTOG criteria and CTCAE V.3.0. Survival events will be assessed by physical examination, serum test, ultrasound of the breast, regional nodes and abdomen every 6 months, breast mammography and chest CT scan annually after completion of RT. Any additional examinations are at the discretion of clinicians. Lymphedema is defined as a ≥10% increase in arm circumference from baseline or the contralateral arm. Radiation-induced skin injuries and upper limb functional impairments are recorded with photographic and video evidence.
Schedule of enrolment, interventions and assessments
Data collection and management
Data collection is facilitated through an eCRF system established by the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. This online system comprises various forms to gather comprehensive data, including baseline information before enrolment, pretreatment assessments, details of the RT plan, acute toxicities, follow-up reviews covering survival and toxicity at specified intervals, quality-of-life assessments using standardised questionnaires and reporting forms for serious adverse events (SAEs). PI, ethical committees and sponsors have unrestricted access to the database for real-time analysis and monitoring. Each participating centre has access to its own data, with the leading investigators being responsible for data quality oversight. On trial completion, data quality and integrity are verified by specially trained personnel before the data set is secured for analysis. All data generated by the study are treated with strict confidentiality. Patient identities will not be disclosed in any public reports or presentations of the study findings. The research centre is obligated to retain all pertinent data for a minimum of 5 years post-study completion. Destruction of data is subject to approval by the ethical committee.
Calculation of samples
The sample size for the trial is calculated using Power Analysis and Sample Size Software (2017) (NCSS, Kaysville, Utah, USA; www.ncss.com/software/pass).
Sample for the ARROW trial
The probability of a type I error is 0.05, and the test power is 80%. The acceptable threshold (δ) is 10%. Previous studies have shown that the incidence of acute radiation-induced toxicity in patients receiving conventional fractionated RNI is 45%.15 22 23 Assuming the incidence of grade 2 or higher acute radiation-induced toxicity is less than 55%, and adopting a non-inferiority test, then a total of 177 patients need to be enrolled. In consideration of an expected dropout rate of 10%, the sample size for this study is determined to be 197 cases.
Statistical analysis
All efficacy and safety analyses will be based on the intention-to-treat principle, and a per-protocol analysis will be performed for the primary endpoint. Acute and late toxicities will be summarised by frequency and severity based on their association with the protocol treatment. To account for differences in toxicity profiles between RT modalities, patients were stratified into two subgroups (IMRT and proton therapy). This stratification ensured independent evaluation of AEs, while controlling for confounding variables such as OARs dosimetry and baseline patient characteristics. Cumulative proportions of time to survival endpoints such as DMFS, IRFS and OS will be described using the Kaplan-Meier method. Severe radiation-related toxicity events will be listed individually. The t-test will be used for the comparison of continuous variables. Statistical analysis will be performed using SPSS software V.21.0 (IBM Corporation, Armonk, New York, USA).
Monitoring
The trial is overseen by a Trial Steering Committee (TSC), with leading investigators from all participating centres. The TSC ensures that the trial follows the protocol and ethical guidelines. Study coordination, monitoring, data acquisition, management and statistical analysis are conducted by a team of statisticians at Ruijin Hospital affiliated with the Shanghai Jiao Tong University School of Medicine. This team ensures the integrity and quality of the data collected throughout the trial. An Independent Data Safety and Monitoring Committee (DSMC) is established to oversee the safety and data quality of the trial. The DSMC monitors the progress of the trial, reviews safety data and assesses the quality of the data. Using the available data, the DSMC makes recommendations to the TSC regarding the continuation of the trial.
Adverse event management
An AE is any unfavourable and unintended sign, symptom or disease that occurs during the trial, regardless of whether it is related to RT. SAEs must be reported to the ethical committee within 24 hours of the PI’s awareness. If an SAE occurs, all antitumour treatments must be halted immediately, and the patient must be monitored until the event is resolved or stabilised, even if it leads to the patient’s withdrawal from the study.
The details of SAEs, including the time of onset, severity, expectedness, duration, measures taken and outcomes, must be meticulously recorded in the eCRF. Reporting of all AEs to the ethical committee and the PI is mandatory at regular intervals, typically every 6–12 months.
Ethics and dissemination
The clinical trial has been approved by the Ethical Committee of Ruijin Hospital affiliated with the Shanghai Jiao Tong University School of Medicine, as well as by the ethical committees of all participating centres. This demonstrates our commitment to conducting research that follows the highest ethical standards. Any changes to the protocol will be carefully documented and submitted for ethical committee review and approval before being implemented. This strict oversight ensures that all trial modifications are in the best interest of the participants and the scientific integrity of the study. The study follows the Declaration of Helsinki and adheres to Good Clinical Practice guidelines to ensure the protection of human rights, safety and well-being of all trial participants.
Participants will provide informed consent before enrolling to ensure full awareness of the study’s objectives, procedures, benefits and risks. On completion of the research, findings will be prepared for submission to peer-reviewed journals. Authorship will be reserved for individuals who have made significant contributions to the study’s design, conduct and analysis. The final clinical study reports and their summaries will be disseminated to the local ethical committees, institutes and sponsors involved in the protocol, ensuring transparency and accountability in the research process.
Patient and public involvement
In the design, execution, reporting and dissemination of our research, we have not engaged patients or members of the public. The research team developed and conducted the study without direct input from these groups.
Discussion
Short-course RT offers several advantages, including reduced use of scarce resources, realised work time and cost savings, increased throughput, reduced waiting times and decreased non-medical expenses for patients.24 Following the publication of the 5-year outcomes from the Fast-Forward trial, there has been a surge of interest in 1-week regimens, prompting the initiation of multiple studies (online supplemental table S6). In these ongoing trials, there are significant variations in the specifications for tumour bed boost and IMNI. Our trial innovates by extending the application of ultra-hypofractionated regimens to sequential tumour bed boosts and IMNI. The ultra-hypofractionated tumour bed boost limits the RT course to a maximum of 1.5 weeks, with a single fractional dose consistent with WBI and RNI, offering a more convenient clinical strategy. The trial also allows the enrolment of patients who have undergone breast reconstruction, received neoadjuvant treatment and those with positive SLN but no ALND. This provides a better representation of the real-world patient population.
The main concern regarding IMNI is the increased risk of cardiac and pulmonary toxicity, especially for left-sided patients. Due to reduced cardiac and lung doses with the use of advanced RT techniques, the overall benefits of IMNI have been demonstrated in multiple prospective clinical trials.2 4–6 20 21 The MA20 study showed a notable improvement in disease-free survival (DFS) for the RNI group, including IMNI, compared with the group without RNI.2 Echoing these findings, the EORTC 22922/10925 study revealed a significant reduction in breast cancer mortality and any recurrence among patients who received RNI, including IMNI.21 25 Furthermore, the DBCG-IMN study substantiated the positive impact of IMNI on reducing the risk of distant recurrence and breast cancer mortality, thereby enhancing long-term survival.5 26 Of note, no excess cardiac mortality with IMNI was observed in these trials.2 5 21 25–27 In light of these findings, the ARROW trial mandates IMNI for all participants, with the expectation that it will yield data on the safety of the ultra-hypofractionated regimen for RNI, including IMNI. Considering the concerns regarding cardiac and pulmonary toxicity, our study protocol included follow-up assessments of cardiac function using electrocardiography and echocardiography, as well as monitoring for radiation pneumonitis using chest CT scans. This can provide more comprehensive safety data for the 1-week regimen of IMNI.
In addition, the ARROW trial allows for the inclusion of patients with positive SLNs but no ALND. The pivotal studies such as Z0011, AMAROS, IBCSG 23-01 and SENOMAC have demonstrated that omission of ALND is non-inferior to ALND in terms of oncological outcomes for patients with 1–2 positive SLNs.28–31 Driven by the findings from these trials, an increasing number of patients with positive SLNs are being spared from ALND in clinical practice. Axillary RT, as demonstrated by the AMAROS trial, was non-inferior to ALND in terms of OS, DFS and locoregional control. Furthermore, axillary RT showed a reduction in the incidence of lymphedema compared with ALND.28 In a prospective screening trial, Naoum et al32 found that the ALND-only group had a significantly higher risk of breast cancer-related lymphedema compared with the group receiving SLN biopsy plus RNI (24.9% vs 10.7%, p=0.02). However, the impact of ultra-hypofractionated RNI, including axillary RT, on oncological outcomes and radiation-induced toxicities such as lymphedema in these patients remains to be determined. The ARROW trial aims to provide preliminary data on the feasibility of ultra-hypofractionated RNI in patients with SLNs but no ALND.
Tumour bed boost has been shown to reduce the local recurrence in high-risk patients undergoing BCS.33 However, determining the optimal fractionation scheme for tumour bed boost in the era of short regimens remains a topic of debate. The Fast-Forward trial adhered to a conventional fractionation approach, prescribing tumour bed boosts of 10 Gy or 16 Gy in 2 Gy fractions sequential to WBI.19 Not all ongoing 1-week regimen trials have disclosed detailed protocols for tumour bed boost. There are also variations in the dose fraction for the tumour bed boost. For instance, the HYPORT trial (NCT03788213) of WBI or chest wall irradiation with or without RNI permits both a simultaneous integrated boost (SIB) of 32 Gy in five fractions and a sequential boost of 12 Gy in four fractions. Another trial of WBI (NCT05586256) offers an SIB of 30 Gy in five fractions or a sequential boost of 7.6 Gy in two fractions. Our trial diverges from other single-week regimen trials by administering a sequential tumour bed boost of 10.4 Gy in two fractions, aligning with the single fractional dose used for WBI and RNI to make it convenient for clinical practice. While SIB offers advantage in reducing overall treatment duration, its safety and efficacy in the context of single-week ultra-hypofractionation remain uncertain. Within the context of an ultra-hypofractionated regimen, incorporating SIB would further increase the fractional dose delivered to the tumour bed, whether this more aggressive approach will increase the risk of late toxicities, such as skin fibrosis and poor cosmetic outcomes, is uncertain as long-term results are insufficient. Considering these factors, at this stage, we prioritised validating the safety of ultra-hypofractionation with a sequential boost which maintains the ultra-hypofractioned size before exploring the feasibility and safety of SIB. We expect to contribute evidence on the safety of a sequential ultra-hypofractionated tumour bed boost and pave the way for future randomised controlled trials evaluating SIB in this context.
One of the critical challenges in implementing ultra-hypofractionated regimens is the high demand for precision in both patient positioning and dose delivery. To address this, we employed daily CBCT imaging, ensuring positional errors in three dimensions do not exceed 3 mm. Additionally, our trial uses IMRT and proton therapy to minimise the dose of OARs as much as possible, particularly for the left-sided IMNI. The decision to use proton therapy or IMRT in this study was based on a structured, patient-centred framework. Proton therapy was prioritised for left-sided IMNI, patients at high risk of radiation-induced toxicity or cases where IMRT plans could not meet heart or lung dose constraints. IMRT was uniformly employed with strict adherence to predefined dose constraints when proton therapy was unavailable due to institutional limitations (eg, lack of proton facilities) or patient-specific barriers (eg, insurance denial despite dosimetric superiority). Patients with IMRT plans exceeding tolerance limits after optimisation were excluded and offered alternative regimens. This dual-tiered approach highlights the real-world complexities of integrating state-of-the-art RT technologies, balancing dosimetric superiority against resource limitations and healthcare inequities. Incorporating daily imaging-guided RT and state-of-the-art RT techniques has the potential to enhance the safety of the ultra-hypofractionated regimen. The technical details in our protocol could provide a framework for the broader clinical adoption of ultra-hypofractionated regimens in the future.
The ARROW trial holds significant importance in exploring the safety and efficacy of ultra-hypofractionated regimens for RNI, including IMN and sequential tumour bed boost in patients with early breast cancer. The results of our trial are expected to pave the way for the broader adoption of ultra-hypofractionated regimens among patients with postoperative RT breast cancer. Furthermore, the IMRT and proton therapy used in our trial can provide more favourable dose distributions for the target volume and OARs, while offering data for implementing an ultra-hypofractionated regimen with these state-of-the-art RT techniques. After confirming the feasibility and safety of this ultra-hypofractionated regimen in the ARROW trial, our team plans to conduct a phase III randomised controlled trial, which will comprehensively evaluate both the efficacy and safety of the 1-week regimen in RNI.
Supplemental material
Ethics statements
Patient consent for publication
Acknowledgments
We thank all the patients who participated in this study and the oncologists, nurses, medical physicists, RT technicians and data managers at the participating centres.
References
Footnotes
JX and SZ contributed equally.
Contributors LC and JC designd the original protocol for the study. JX and SZ contributed to study management and drafted the manuscript. W-XQ performed the sample size calculation and data analysis. All authors participated in enrolment and follow-up of patients. All authors read and approved the final manuscript. JC is the guarantor.
Funding This study was supported in part by the Shanghai Science and Technology Innovation Action Plan (grant number 23Y41900100), Clinical Research of Shanghai Municipal Health Commission (grant number 20224Y0025), National Natural Science Foundation of China (grant number 82373514, 82373202), National Key Research and Development Program of China (grant number 2022YFC2404602) and Shanghai Hospital Development Center Foundation (grant number SHDC12023108).
Disclaimer The funding sources had no role in the study design, data collection, data analysis, data interpretation or writing of the report.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.