Hypofractionated Radiotherapy After Breast Reconstruction for Breast Cancer

Breast cancer is one of the most common malignant tumors among women worldwide. For high-risk patients who undergo total mastectomy, postoperative radiotherapy can significantly reduce the local recurrence rate and improve survival rates. With the advancement of treatment and the increasing demands of patients for quality of life, breast reconstruction surgery has become increasingly popular, which greatly improves the psychological and social status of patients.

Currently, post-reconstruction radiotherapy for breast cancer is mostly carried out using a conventional fractionation scheme (such as 50 Gy/25 times, lasting 5 weeks), which is long in duration and burdensome, affecting patient compliance and occupying a large amount of medical resources. Large fractionation radiotherapy can significantly shorten the treatment course by increasing the single dose and reducing the number of treatments (such as 43.5 Gy/15 times, lasting 3 weeks). Its application has a solid theoretical basis: breast cancer has a relatively low α/β value (about 3-4 Gy), and moderately increasing the single dose may enhance the killing effect on the tumor. In patients after breast-conserving surgery and modified radical mastectomy, large-scale phase III clinical trials (such as START, Wang SL, etc.) have confirmed that the long-term efficacy and safety of large fractionation radiotherapy are comparable to those of conventional fractionation, so the international authoritative consensus (such as ESTRO) has supported its use for chest wall irradiation.

However, when radiotherapy is combined with breast reconstruction, the situation is more complex. Radiotherapy may affect tissue healing, increasing risks such as capsular contracture, infection, prosthesis exposure, and reconstruction failure. Currently, high-level evidence is mostly derived from patients without reconstruction. Although retrospective studies suggest that the complication rate after using a large fractionation scheme (such as 40 Gy/15 times) in patients after reconstruction may be comparable to or even lower than that of conventional fractionation, and the radiotherapy dose and complication risk may have a positive correlation, these conclusions are not consistent and lack conclusive evidence from prospective randomized controlled trials. This is the current key evidence gap in clinical practice.

In addition, post-reconstruction radiotherapy requires high technical requirements and needs to follow specific consensus on target area delineation (such as the ESTRO guidelines) to ensure coverage of common recurrence sites such as skin and subcutaneous tissues, and the use of intensity-modulated radiotherapy and other technologies to ensure uniform and sufficient target doses while strictly protecting vital organs such as the heart and lungs.

In conclusion, although large fractionation radiotherapy shows advantages in a wide population of breast cancer patients, its long-term efficacy and safety in patients after breast reconstruction, especially its impact on the reconstruction outcome, have not been clearly verified through phase III randomized controlled trials. Therefore, conducting a head-to-head comparison III phase clinical trial is crucial to provide an efficient and safe optimized radiotherapy scheme for this growing patient group, fill the evidence gap in evidence-based medicine, and provide direct evidence for clinical guidelines.

Project Introduction:

Research Objective:

This study aims to evaluate the efficacy and safety of large fractionation radiotherapy (40 Gy/15 times) compared to conventional fractionation radiotherapy (50 Gy/25 times) in breast cancer patients undergoing breast reconstruction through a phase III randomized controlled, non-inferiority clinical trial. The main objective is to verify that large fractionation radiotherapy is not inferior to conventional fractionation radiotherapy in local area control; the secondary objectives are to compare the main complications of wounds, acute and chronic toxic reactions, breast cosmetic effect, and quality of life between the two groups, thereby providing high-level evidence-based medical evidence for optimizing postoperative radiotherapy schemes and promoting individualized treatment. In addition, molecular characteristics of blood samples will be studied to search for biomarkers related to the radiotherapy process and treatment response, providing high-level evidence for medium-dose low-fractionation radiotherapy after different reconstructions. Total mastectomy (with or without preservation of the nipple-areola complex) + axillary lymph node dissection/ sentinel lymph node biopsy + implant/expander placement R0 resection (negative margins) pT3 or N2-3 stage or pT1-2N1 disease; no distant metastasis; completed standard neoadjuvant/adjunctive chemotherapy cycles; signed informed consent form;

Treatment plan:

This study is a phase III, randomized, controlled clinical trial, planned to be conducted in a single center, involving patients who underwent breast reconstruction after breast cancer surgery. A total of 812 cases are planned to be included.

Patients meeting the criteria were randomly assigned 1:1 to the hyperfractionated radiotherapy group and the conventional fractionated radiotherapy group. The radiotherapy plan for the conventional fractionation group: 50Gy/25F/5w, the radiotherapy plan for the hyperfractionation group: 40Gy/15F/3w. Stratified design: immediate prosthesis implantation, immediate autologous tissue implantation, delayed-immediate reconstruction. The stratification was balanced at random inclusion.

Target area: chest wall, supraclavicular lymph drainage area, and axillary lymph drainage zone III. Radiotherapy technique: VAMT or TOMO. According to the NCCN guidelines, all patients receive chemotherapy, and receive corresponding endocrine and targeted therapy based on hormone receptor status and HER-2 status. Two years after the end of treatment, re-examination is conducted every 3 months, every 6-12 months after 3-5 years, and once a year thereafter. Acute radiotherapy reaction rating according to CTCAE 3.0 standard, late radiotherapy reaction evaluation according to RTOG standard.

Efficacy observation:

Main observation indicators:

• Local control rate: The local control rate is one of the key indicators for evaluating the effect of radiotherapy after breast cancer surgery, directly affecting the prognosis of patients. The main purpose of radiotherapy is to control local recurrence, reduce the proliferation and metastasis of tumor cells. The local control rate is usually evaluated through follow-up to determine whether local recurrence occurs.

Local recurrence rate: Regularly detect the recurrence of tumors in the breast area through imaging examinations (such as mammography, MRI, ultrasound). Local recurrence is defined as the re-occurrence of a tumor at the primary tumor site or the breast reconstruction area, or confirmed malignant tumor cells through biopsy. Recurrence time: The time of local recurrence, usually determined through follow-up records, as an important indicator for local control.

• Complications after breast reconstruction surgery Complications after breast reconstruction surgery, referring to core complications that affect the survival of reconstruction, require secondary surgery or significantly affect the patient's quality of life. Severe capsular contracture rate: This is the main physical failure mode of prosthesis reconstruction. Reconstruction failure rate: The need for secondary surgery to remove the prosthesis or replace the flap.

Secondary observation indicators

• Survival rate
• Radiotherapy-related side effects
• Quality of life
• Treatment adherence during radiotherapy
• Precision of radiotherapy dose and treatment plan
• Economic analysis of radiotherapy
• Incidence of adverse reactions

Inclusion criteria

• Female, aged 18 - 75 years
• Karnofsky score ≥ 60
• Invasive breast adenocarcinoma confirmed by histopathology
• Total mastectomy (with or without preservation of nipple-areola complex) + axillary lymph node dissection/ sentinel lymph node biopsy + R0 implantation/expansion placement (negative margins) pT3 or N2-3 stage or pT1-2N1 disease
• No distant metastasis
• Completed standard neoadjuvant/adjunctive chemotherapy cycles
• Signed informed consent form

Exclusion criteria

• If a patient has bilateral breast cancer, they will be excluded; those with distant metastasis or metastasis in the supraclavicular or internal mammary lymph nodes; those who have received radiotherapy in the past; those who have had or are currently suffering from malignant tumors, except for non-pigmented skin cancer; those who are pregnant; those with active collagen vascular diseases or other serious diseases, such as alcohol and drug abuse or mental disorders.
• Patients with severe dysfunction of the heart, liver, or kidneys.
• Patients with a history of radiotherapy or those who are contraindicated to radiotherapy.
• Pregnant or lactating women.
• Patients with severe mental or psychological disorders who cannot fulfill the requirements of the study.
• Other patients with serious diseases that cannot meet the requirements of the study.