Participants, Interventions and Outcomes
Study Setting {9}
The trial is supported currently by intramural funding from Tata Medical Center and has received extramural funding from the NAG foundation. The study has been initiated at the Department of Radiation Oncology at Tata Medical Center. Site initiation has been done at CMC Vellore and SGPGI Lucknow. Combining all three centres, approximately 100 patients annually undergo adjuvant radiotherapy. As the eligibility criteria are very inclusive we expect that most breast cancer patients requiring adjuvant radiotherapy will be eligible for inclusion in this study. Other large academic centers treating a substantial number of breast cancer patients will be approached for participation in the future.
Eligibility Criteria {10}
Patient Eligibility Criteria:
Inclusion criteria are deliberately kept non-restrictive so that the results can be generalizable to the Indian population of breast cancer patients. Patients who have undergone curative intent surgery in the form of a mastectomy or breast conservation surgery with clear margins for non-metastatic invasive breast cancers are eligible for this trial. An adequate axillary clearance or an appropriate axillary staging procedure like sentinel lymph node biopsy should have been performed. All patients undergoing breast conservation or neoadjuvant chemotherapy will be eligible. Patients will be eligible for inclusion after mastectomy if they have the following characteristics:
- T3 - T4 tumors
- > 3 axillary lymph nodes
- T0-T2 tumour with 0 - 3 axillary lymph nodes with a Cambridge Score of 3 or more(30).
The primary exclusion criteria are patients with carcinoma in situ, non-epithelial breast primaries and metaplastic carcinomas. Patients with a residual internal mammary node or supraclavicular fossa node prior to radiotherapy will also be excluded as they may be eligible for an additional boost to the residual node. Patients with prior radiotherapy to the breast or those planned for concurrent chemotherapy will also be excluded.
Trial Center Requirements
High volume centers treating more than 150 breast cancer patients annually with facilities for surgery, radiotherapy, chemotherapy as well as a functional pathology and radiology services will be required. Ideally there should be a dedicated multi-disciplinary team comprising of surgeons, clinical/radiation oncologists, medical oncologists, pathologists and radiologists treating breast cancer. The center should report mammograms using the Breast Imaging Reporting and Data (BIRAD) system. Breast pathology services should have accredited services for evaluation of Estrogen receptor, Progesterone receptor and Her2neu receptor status with immunohistochemistry.
For this study, breast cancer patients must be simulated through a volumetric imaging technique. The trial centres must fulfil the trial quality assurance requirements as outlined in the Radiotherapy Quality Assurance (RTQA) document.
Who will take informed consent {26a}
Informed consent will be obtained from the patient by the investigators or designated authorized person. Written informed consent will be obtained on the informed consent form.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Biospecimen banking in the form of plasma and buffy coat will be done for consenting patients. A separate consent will be obtained by the investigators for this. The biobanking consent form used in TMC will be used for specimen biobanking in Tata Medical Center. For other centres, biobanking of biological specimens will be done at investigators’ discretion following institutional policy.
Interventions
Explanation for the choice of comparators {6b}
One week hypofractionated radiotherapy is likely to become the standard for delivery of breast adjuvant radiotherapy if the results of the FAST Forward trial support the primary objective. Hence the current trial will also test a one-week regimen. The three-week course of radiotherapy used in the control arm has already demonstrated non-inferiority in terms of oncological outcomes in the START trials. Currently, this is the standard radiotherapy schedule used for most breast cancer patients in the participating centers.
Intervention Description {11a}
Overview
Patients will be randomized into two arms equally:
- Control Arm: 40 Gy in 15 fractions over 3 weeks to the whole breast or chest wall. Patients undergoing breast conservation therapy will receive additional boost radiotherapy to the tumour bed. The supraclavicular fossa will be treated in patients with node-positive disease or those receiving neoadjuvant chemotherapy. IMC and Axillary radiotherapy will be given as per the institutional policy. Boost radiotherapy will be delivered using SIB of 8 Gy in 15 fractions (or alternatively using a sequential boost of 12 Gy in 4 fractions)
- Test Arm: 26 Gy in 5 fractions over 1 week to the whole breast or chest wall. Treatment volumes will be the same as the control arm. Additional boost will be delivered to patients who have undergone breast conservation. Boost radiotherapy will be delivered using SIB of 6 Gy in 5 fractions (or alternatively using a sequential boost of 12 Gy in 4 fractions)
Radiotherapy
Radiotherapy should be started within 12 weeks of the last date of surgery or last cycle of planned adjuvant chemotherapy. All patients would be treated on linear accelerators (6 - 15 MV energies). Radiotherapy planning would be performed on volumetric planning CT scans with a pre-defined simulation protocol. Patients with left sided breast cancers should preferably receive cardiac sparing radiotherapy. Field based planning for the breast and chest wall is allowed in the protocol where anatomical landmarks are identified and coverage ensured. This is the current practice in most of the centers in this trial.
The organs at risk to be delineated include the ipsilateral and contralateral lung, heart, and the contralateral breast. In patients undergoing radiotherapy for left sided breast, the left anterior descending artery may also be delineated (31). The brachial plexus may be delineated in patients undergoing regional nodal radiation (32).
Tangential beams would be utilized for irradiating the breast or chest wall, while regional nodal radiation should be delivered using a technique that ensures no overlap of the field - in most patients, this would imply a enface field to cover the supraclavicular fossa (SCF) with a half beam block or a collimator-couch rotation based technique. Dose will be prescribed at a point in the midplane for the breast and chest wall for tangents. For patients receiving SCF radiation, the dose will be prescribed at the depth of maximum dose (Dmax). In patients who have undergone breast conservation, boost will be delivered using the technique used in the institute. Use of a volumetric modulated arc therapy (VMAT) based Simultaneous Integrated Boost (SIB) for tumor bed irradiation is allowed. Inverse planned radiation is allowed for patients receiving radiation to the internal mammary nodal chain.
Dose in the target volume should be homogenous and use of a forward planned field in field IMRT technique is allowed. Alternatively centers can specify the technique to be used for ensuring dose homogeneity. Individualized treatment planning will be done with a target to ensure that the breast/chest wall is covered with 95% of the prescribed dose and that the maximum dose does not exceed 107% of the prescribed dose. In patients undergoing VMAT simultaneous tumour bed boost (SIB), the dose to the boost target volume will be restricted to < 107% of the total dose.
Table 2 shows the dose constraints to be used for plan evaluation. BTV = Boost Target Volume, D98 = Dose to 98% volume, D95 = Dose to 95% volume, D2 = Dose to 2% volume, D0.03 = Dose to 0.03 cc, V10 = Percentage volume receiving 10 Gy, V2 = Percentage volume receiving 2 Gy, V7 = Percentage volume receiving 7 Gy, V1.2 = Percentage volume receiving 1.2 Gy, V12 = Percentage volume receiving 12 Gy, V8 = Percentage volume receiving 8 Gy.
Volume
|
Standard Arm
|
Test Arm
|
Criteria
|
Mandatory
|
Optimal
|
Criteria
|
Mandatory
|
Optimal
|
BTV (only in patients receiving SIB)
|
D98
|
≥ 43.2 Gy
|
NA
|
D98
|
≥ 28.8 Gy
|
NA
|
D95
|
≥ 45.6 Gy
|
NA
|
D95
|
≥ 30.4 Gy
|
NA
|
D2
|
≤ 51.4 Gy
|
≤ 50.4 Gy
|
D2
|
≤ 34.2 Gy
|
≤ 33.6 Gy
|
D0.03
|
≤ 52.8 Gy
|
≤ 51.4 Gy
|
D0.03
|
≤ 35.2 Gy
|
≤ 34.2 Gy
|
Heart
|
Mean
|
≤ 2.5 Gy
|
≤ 2 Gy
|
Mean
|
≤ 1.6 Gy
|
≤ 1.3 Gy
|
V10
|
≤ 5%
|
≤ 3%
|
V7
|
≤ 5%
|
≤ 3%
|
V2
|
≤ 30%
|
≤ 20%
|
V1.2
|
≤ 30%
|
≤ 20%
|
Ipsilateral Lung
|
V12
|
≤ 30%
|
≤ 18%
|
V8
|
≤ 30%
|
≤ 18%
|
Treatment will be delivered 5 days a week treating one fraction a day. All fields will be treated together. Dosimetric quality assurance of all plans will be performed with point dose measurements along with fluence profile checks if IMRT is used. The center will prespecify the imaging verification protocol to be used for their patients.
Criteria for discontinuation and modifying allocated interventions {11b}
Breast cancer radiotherapy is not expected to result in substantial acute toxicity. Treatment should not be interrupted unless a patient has a Grade III-IV CTCAE adverse event. After this treatment can be restarted once the toxicity has reduced to Grade I or less and if in the treating physician’s opinion it is safe to continue with treatment.
Strategies to improve adhere to intervention {11c}
Patients will be counselled about the need to adhere to the treatment schedule. They will be reviewed weekly during treatment to discuss and manage any treatment related adverse events they may be encountering. Any missed fraction would be informed to the treating team and attempts will be made to communicate with the patient to avoid this in future.
Relevant concomitant care permitted or prohibited during the trial {11d}
No specific contraindications to any medication except for the receipt of concurrent chemotherapy. Patients may continue with planned endocrine therapy and anti-HER2 therapy during the course of radiotherapy.
Provisions for post-trial care {30}
Routine follow up care will be provided for all patients including appropriate clinical evaluation, adjuvant endocrine therapy, maintenance anti-HER2 therapy as well as chemotherapy as required. Compensation for trial related injuries will be provided as per extant Indian laws after the review by the Institutional review board.
Outcomes {12}
Primary Outcome
The primary outcome of interest is the locoregional recurrence, which is defined as any invasive recurrence in the ipsilateral breast or chest wall or ipsilateral axillary, supraclavicular or internal mammary lymph nodes (ipsilateral lymph nodes level 1 - 4 and internal mammary nodes as defined by Offersen et al(34)). Cumulative proportion of patients with locoregional recurrence at 5 years will be estimated and hazard ratio of the locoregional recurrence rate between the two groups will be reported.
Secondary Outcomes
- Overall survival: This is defined as the interval of time between the date of randomization to the date of death due to any cause. We will attempt to obtain the reason for death wherever feasible. The duration will be calculated using the actuarial method and patients who are alive at last follow up will be censored on the same date. Cumulative proportion of patients surviving at 5 years will be reported along with hazard ratio for the two arms.
- Invasive disease free survival: This is defined as the time from randomization to the time any recurrence (pre-invasive / invasive), distant metastases, death from any cause and second invasive primaries, including invasive neoplasms of the breast. Cumulative proportion of patients without invasive disease recurrence at 5 years will be reported along with hazard ratio for the two arms.
- Adverse Events (AE): The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be used to classify and grade the severity of adverse events. Clinician reported AE grades would be collected in addition to patient reported outcomes measures to be collected as a part of assessment of Quality of Life. Adverse events due to radiotherapy (CTCAE 5.0) will be classified into the following categories:
- Start of RT to 90 days after RT: Acute toxicity
- > 90 days after RT: Late toxicity.
- Quality of Life: Quality of life will be assessed using self administered EORTC QLQ C30 and the FACT-B questionnaires before the start of radiotherapy, at the end of radiotherapy and then at 6, 12 and 18 months. While various QoL endpoints are of interest, the primary QoL endpoint of interest will be the summary score of EORTC QLQ C30 derived from 15 questions as defined by Giesinger et al(37). We will be comparing the proportion of patients in whom the summary score of the EORTC QLQ C30 is equal to or better than the baseline at 12 months in the two arms.
Participant Timeline {13}
The participant timeline for treatment and assessments is shown in the table below.
Assessment
|
All follow-up time points are taken from the date of completion of RT
|
Baseline
|
Adjuvant RT
|
3 - 12 months every 3 months after RT
|
13 - 60 months every 6 months after RT
|
Wk 1
|
Wk 2
|
Wk 3
|
Clinical Evaluation
|
X
|
|
|
|
|
|
Eligibility Checklist
|
X
|
|
|
|
|
|
Informed Consent
|
X
|
|
|
|
|
|
Randomization
|
X
|
|
|
|
|
|
RT QA
|
Prior to center initiation and throughout the trial recruitment period
|
RT Treatment (Control Arm)
|
|
X
|
X
|
X
|
|
|
RT Treatment (Test Arm)
|
|
X
|
|
|
|
|
RT Verification (Control Arm)
|
|
X
|
X
|
X
|
|
|
RT Verification (Test Arm)
|
|
X
|
|
|
|
|
SAE
|
|
X
|
X
|
X
|
X
|
X
|
Acute Toxicity
|
|
X
|
X
|
X
|
|
|
FU Assessments
|
|
|
|
X
|
X
|
X
|
EORTC QLQ C30 (Control Arm)
|
X
|
|
|
X
|
At 6, 12 and 18 months after completion of RT
|
FACT-B (Control Arm)
|
X
|
|
|
X
|
At 6, 12 and 18 months after completion of RT
|
EORTC QLQ C30 (Experimental Arm)
|
X
|
X
|
|
|
At 6, 12 and 18 months after completion of RT
|
FACT-B (Experimental Arm)
|
X
|
X
|
|
|
At 6, 12 and 18 months after completion of RT
|
Note that patients who undergo sequential tumor bed boost will have their post radiotherapy assessment postponed till boost is completed. This would mean at the 2nd week in patients receiving 1 week RT and the 4th week in patients undergoing 3 week RT. RT = Radiotherapy, FU = Follow up , EORTC QLQ C30 = European Organization for Research and Therapy of Cancer Quality of Life Questionnaires C30, FACT B = Functional Assessment of Cancer Therapy - Breast.
In each study visit a clinical assessment including a history and examination will be undertaken. Adverse events related to radiotherapy will be recorded in a case record form. Quality of life questionnaires will be administered on the visits as indicated. During the follow up period patients will undergo mammogram of intact breast(s) at 12 - 18 month intervals or as per the institutional policy.
Sample Size {14}
Non-inferiority margin and justification for the same
While patients in India do present at a younger age and with advanced disease, locoregional recurrence rates are comparable to stage matched caucasian patients. An audit of locoregional recurrence rates in our population suggests that locoregional recurrence free survival rate was 97.1% at 3 year (33). Recent data from SGPGI also suggests that 4 year local recurrence free survival of 97% was reported (34). Assuming that the locoregional recurrence rate in the control arm is 5%, a non-inferiority boundary of 3% is clinically acceptable and corresponds to a hazard rate of 1.63. The choice of the non-inferiority boundary is arbitrary to a significant extent and we base it on the guidance that it should not be larger than the expected benefit from adjuvant radiotherapy. A large volume of data is available regarding the benefit of adjuvant radiotherapy in breast cancer patients. In the setting of breast conservation surgery, the EBCTCG meta-analysis demonstrated that use of adjuvant radiotherapy reduced the 5-year local recurrences by 17 % after breast conservation surgery(2), while in the postmastectomy setting the 5-year local recurrence was reduced by 14.7% for N+ patients(3). The START trials were designed to show a difference of 5% as the non-inferiority boundary(35). This is approximately 33% of the benefit that can be expected from RT vs no RT. Since the START trials have demonstrated that the 40 Gy is non-inferior to 50 Gy we can thus consider a non-inferiority boundary of 3% as appropriate for this study.
Sample size
The sample is calculated based on the assumption that the 5 year local recurrence rate in the control arm is 5% with an exponential distribution. We hypothesize that the use of 1 week course of adjuvant radiotherapy will not increase the locoregional recurrence beyond 8% (absolute difference of 3%), corresponding to a hazard ratio of 1.63. We further assume that patients will be accrued over 5 years with an initial ramp up in the first year and that 2% of the patients will be lost to follow-up each year of the trial. The total trial duration is expected to be 10 years to ensure a minimum follow up of 5 years for the last patient. For a fixed sample size design to achieve the required number of events to achieve a one sided Type I error of 0.025 and a power of 80% the total number of events required is 140. The total planned sample size is 2100 patients.
Recruitment {15}
Patients will be recruited from the outpatient departments of the disease management group at each institute. No advertising is permitted for recruitment and no inducements will be given for recruitment of patients in the study. Central randomization will be done at Tata Medical Center using permuted block randomization.
Assignment of interventions: allocation
Sequence generation {16a}
Stratified randomization using permuted blocks will be used for randomization. The randomization sequence will be generated using the Robust Randomization App (available at https://clinicalresearch-apps.shinyapps.io/rrapp/) or a similar application and the randomization scheme generated from the app will be then used with the RedCap Randomization module to generate the randomization sequence. Patients will be allocated into the two groups in a 1:1 ratio. The following stratification factors will be used:
- Type of Surgery: Mastectomy or Breast Conservation
- Regional Nodal Radiation: Required or Not
- Triple Negative Breast Cancer: Yes or No
- Institute
Concealment mechanism {16b}
Randomization of the patient will be done using the randomization module implemented in the RedCap randomization module in the study database. Central randomization will be done to ensure allocation concealment.
Implementation {16c}
After screening and eligibility checks are completed, consenting patients will be randomized using the randomization module. The randomization will be done centrally at Tata Medical Center. RedCap provides a data access group feature which ensures that randomization is stratified by the institute. After filling the other stratification factors, the randomize button will be clicked which will then provide the arm allocation information. This information is permanently recorded in the database and cannot be altered in future.
Assignment of interventions: Blinding
Who will be blinded {17a}
Given the nature of intervention used in the study, no blinding is planned in this study.
Procedure for unblinding if needed {17b}
As blinding is not being done in this trial, no unblinding will be required.
Data collection and Management
Plans for assessment and collection of outcomes {18a}
Data related to the trial will be collected and maintained on a RedCap database maintained in Tata Medical Center. The randomization module of RedCap will be used for random allocation into the two arms. Participating institutes will have access to the RedCap data entry system. The RedCap data forms can be printed out and used as such for clinical data entry in the trial if paper form entry is needed. The following forms will be created in Redcap for the data collection purpose:
- Demographic Information
- Trial screening form
- Pretreatment assessment
- Radiotherapy plan details
- Radiotherapy plan QA details
- Radiotherapy treatment setup inaccuracy data
- Radiotherapy treatment review form
- Follow up review form
- Outcome form.
- QoL capture form
- SAE reporting form
The RedCap features for longitudinal data collection as well as repeating forms will be utilized for data collection. RedCap also has the facility to set up rules for data quality assurance which will be used to ensure that entered data is of high quality. Planning CT and treatment plan data will be archived in an image bank which is concurrently undergoing development in our institute (36).
Plans to promote participant retention and complete follow-up {18b}
If a patient or investigator decides to stop the study treatment then the patient’s health status will be periodically reviewed via continued study visits or phone contact, or from their general practitioner or medical records to allow collection of outcomes data. Follow-up assessments including completion of the quality of life questionnaires should still be completed if the patient is willing.
In the event that a patient withdraws from the study entirely, the effective date of the notification will be the date on which their withdrawal is received by the study team. No information about the patient will be collected from that point in time onwards but any information collected prior to that date can be used and forms part of this study.
For patients moving from the area during follow up, every effort should be made for the patient to be followed up at another participating trial centre and for that trial centre to take over responsibility for the patient. A copy of the patient Case Record Forms (CRF) will need to be provided to the new site after appropriate patient consent. Until the new centre agrees (in writing) to take over responsibility, the patient remains the responsibility of the original centre.
Data management {19}
Access to the data will be available to the principal investigator of the study as well as to the co-investigators at the end of the trial. The data quality and integrity will be checked at quarterly intervals using the data quality checking system available in Redcap. Patient identifiers will be noted as such in the Redcap database and the same will be used for ensuring that any data exports contain de-identified data only. Institutes will have access to the data of their own institute during the trial phase. Once the trial is completed the main database will be checked for data consistency and quality and then closed for analysis. Additionally, the PI will be asked to sign off key CRFs electronically to ensure completeness and accuracy of the data.
Source documents pertaining to the trial must be maintained by investigational sites. Source documents may include a subject's medical records, hospital charts, clinic charts, the investigator's subject study files, as well as the results of diagnostic tests such as X-rays, laboratory tests, and electrocardiograms. The investigator's copy of the case report forms serves as part of the investigator's record of a subject's study-related data. All study-related documentation will be maintained for 10 years following completion of the study or according to existing regulatory requirements.
The following information should be entered into the subject's medical record:
- Subject’s name, contact information and protocol identification.
- The date that the subject entered the study, and the subject number.
- A statement that informed consent was obtained (including the date).
- Relevant medical history
- Dates of all subject visits and results of key trial parameters.
- Occurrence and status of any adverse events.
- The date the subject exited the study, and a notation as to whether the subject completed the study or reason for discontinuation
Confidentiality {27}
The study will be conducted in accordance with applicable rules and regulations. All data generated in this study will remain confidential. All information will be stored securely at the sponsoring institute and will only be available to staff directly involved with the study. For documents transferred between institutions the data will be securely stored in the RedCap database and access restricted to the trial institute and the CTU through the use of the data access groups features in RedCap.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Blood will be collected at the beginning and end of radiotherapy for consenting patients. 10 mL of venous blood will be collected and stored in a Ethylene Diamine Tetraacetate (EDTA) blood tube. The sample will be processed for storing the plasma and buffy coat separately in the biobank. Future studies will be designed to utilize these biospecimens for correlative translational studies investigating fraction sensitivity.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The experimental arm will be compared against the control arm for all primary analyses.
Cumulative proportions of time to event endpoints will be reported using Kaplan Meier method. As there is a potential that the patients may go off study after detection of a recurrence hence this method is being adopted. The Kaplan Meir estimate of cumulative proportion generally gives a higher estimate of the event rate in presence of competing risks. The hazard ratio and the 95% confidence intervals for the locoregional recurrence rate will be computed using the Cox regression analysis. The upper bound of the 95% confidence intervals would be used to demonstrate non-inferiority for locoregional recurrence which would be concluded if the same exceeds the predefined threshold of 1.63. The Chi-square test with continuity correction will be used for comparing the binary / categorical variables, while the Wilcoxon test will be used for comparing continuous variables.
All tests will be two-sided and a significance level of 5% will be used for declaring statistical significance. The proportion of patients experiencing any Grade 3 - 4 AE will be reported in each arm and compared between the two arms using the Chi-square test or Fisher's exact test. Similar comparisons will be done for each AE term between the two groups. Comparison of AE between the two arms will be done on full analysis set as well as the per-protocol set.
Multivariable analysis for the primary and secondary endpoints will be conducted using Cox regression analysis. For every model, the underlying assumptions for the model will be checked which would include checks for proportional hazards assumptions, outlier and overly influential detection as well as a check for the linearity assumptions. Additionally bootstrapping will be used to estimate the calibration and discrimination of the model. Further details can be found in the statistical analysis plan.
Interim analyses {21b}
An interim analysis for safety will be planned at 3 years when 16 events (locoregional recurrences) in total are expected to have occurred. The critical Z value at the time of interim analysis is 3.47 for futility. The following table illustrates the key features of the design
Analysis
|
Value
|
Efficacy
|
Futility
|
IA1
|
Z
|
3.47
|
-1.48
|
N:1184
|
p(1-sided)
|
0.0003
|
0.9318
|
Events: 16
|
HR at bound
|
0.28
|
3.47
|
Year: 3
|
P(cross) if HR = 1.63
|
0.0003
|
0.07
|
|
P(cross) if HR = 1
|
0.0056
|
0.008
|
Final
|
Z
|
1.96
|
1.96
|
N: 2100
|
p(1-sided)
|
0.025
|
0.025
|
Events: 140
|
HR at bound
|
1.17
|
1.17
|
Year: 10
|
P(cross) if HR = 1.63
|
0.025
|
0.975
|
|
P(cross) if HR = 1
|
0.800
|
0.200
|
Asymmetric two-sided group sequential design with binding futility bound, 2 analyses, time-to-event outcome with sample size 2100 and 140 locoregional recurrence events required, 80 percent power, 2.5 percent (1-sided) Type I error to detect a hazard ratio of 1 with a null hypothesis hazard ratio of 1.63. Enrollment and total study durations are assumed to be 5 and 10 years, respectively. Efficacy bounds derived using a Lan-DeMets O'Brien-Fleming approximation spending function. Futility bounds derived using a Lan-DeMets O'Brien-Fleming approximation spending function.
An interim analysis will also be planned once 50 patients are accrued in each arm and in this analysis, we will be evaluating the acute toxicity of the two interventions. The sample size of 50 patients in each arm allows us 80% power to exclude a within-group rate of CTCAE Grade 3 or more acute skin toxicity exceeding 10% over the target rate of 5% (one-sided type I error of 5%) ie. 15%.
Methods for additional analyses (e.g. subgroup analyses) {20b}
The following pre-specified subgroup analyses will be conducted on the primary and the other time to event endpoints stratified by:
- Menopausal Status: Premenopausal vs Postmenopausal
- Nodes Positive: None vs 1 - 3 vs > 3
- Subtype: Luminal vs Her2-enriched vs TNBC
- Regional Nodal Radiation: None vs SCF alone vs IMN + SCF
- Boost Type: SIB vs Sequential Boost
These subgroups are chosen as they have an implication on the primary as well as the secondary time to event outcomes and are independently prognostic. Results will be presented as forest plots with interactions results alongside. The interaction test will test if the treatment effect is modified by the subgroup.
In order to evaluate the impact of prognostic factors on the treatment effect, a nomogram will be built using Cox regression that includes treatment as a factor. The use of this nomogram will enable the user to judge the benefit arising from the use of a particular fractionation regimen in a patient with a given combination of prognostic factors.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
For time to event endpoints, we will censor the patient at the date of last follow up unless the patient is documented to have an event. We will attempt to contact the patients telephonically or by other methods to ensure adherence to follow up. If more than 10% of the patients have missing data then an additional sensitivity analysis will be undertaken where all lost to follow up patients would be assumed to have the event of interest. For quality of life data, we will under complete case analysis and as a sensitivity analysis missing values will be imputed using an imputation based approach.
Finally, as this is a non-inferiority trial, if there is high non-compliance with the test treatment, then an analysis of only those receiving per-protocol treatment will be conducted separately.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The full protocol as well as the statistical analysis plan is available as supplementary material with the manuscript. At present there are no plans to make patient level data available publically but we will consider the same once primary reporting of the outcomes is completed or as mandated by regulations.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The trial will be managed through the CTU at the Tata Medical Center. All PIs of the collaborating institutes will be a part of the trial management committee. Study coordination, monitoring, data acquisition and management and statistical analysis will be performed by Tata Medical Center.
Additionally, we will constitute an outcome assessment committee who will provide independent and central assessment of the important trial outcomes.
Composition of the data monitoring committee, its role and reporting structure {21a}
An independent data safety and monitoring committee will be constituted which will provide an independent assessment of the patient safety, trial progress, making recommendations to the trial management committee about the continuation of the trial based on the data made available by the trial investigators. The DSMC will also recommend any revisions in protocol required as a result of new or emerging information regarding the adjuvant radiotherapy schedule for this setting. DSMC reports will be communicated to the institutional review boards of the participating centers. The DSMC will be composed of four to five members of whom at least one will be a statistician with significant experience in clinical trials.
Adverse event reporting and harms {22}
All adverse events related to radiotherapy as well as any serious adverse events will be recorded in clinical trial forms which will be recorded in the centrally managed RedCap database. The investigator at each site will be responsible for reporting the SAE to the respective Institutional Review Board as well as the PI at the CTU. Local IRB would be notified of any SAE within 24 hours on a working day or as per the institutional norm. The sponsor will be intimated within a period of 10 days from the date of occurrence of the SAE. SAEs must be reported up to 30 days from the end of study intervention.
The following information should be provided for all SAEs:
- Event description including classification according to NCI CTCAE
- Primary and secondary diagnosis of the event (If death/hospitalisation)
- Severity / Worst Grade
- Attribution to study intervention
- Expectedness (listed in IB/product information)
- Action taken with study intervention
- Impact of SAE (e.g. hospitalisation details)
- The outcome of SAE including end date if recovered
Frequency and plans for auditing trial conduct {23}
Compliance to protocol will be reviewed after accrual of the first 5, 25, 75 and 200 cases. Any protocol deviation needs to be notified to the respective IRB, to the chief investigator, coordinating centre and discussed in the trial management committee meetings. Additionally, PI at each center should be notified about any changes made to the protocol in the interest of patient safety as a result of this- this will need updating in writing in the trial protocol with a change in the version number of the study protocol. Any major radiation dosimetric protocol deviation in more than 1 patient of the first 5 patients or more than 10% cases after 10 have been recruited, should be informed and discussed in the trial management committee. Additional audits and monitoring as required by trial sponsors would be done as mandated by institutional and regulatory norms.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Changes and amendments to the protocol would only be made by the Trial Management Committee. Approval of amendments by the Institutional (IRB) would be required prior to their implementation. In some instances, an amendment may require a change to a consent form. In such cases, the form will be used only after approval from the IRB. All amendments will be stored in the sponsor site and will be shared with all participating sites through email as well as during regular trial management committee meetings.
Dissemination plans {31a}
A Clinical Study Report which summarises and interprets all the pertinent study data collected will be issued which may form the basis of a manuscript intended for publication. The Clinical Study Report or summary thereof will be provided to the local IRB of the institutes participating in the protocol. Additionally the same will be made available on the trial registration websites. The Trial Management Committee will appoint a Writing Committee to draft manuscript(s) based on the trial data. Manuscript(s) will be submitted to peer-reviewed journal(s). The Writing Committee will develop a publication plan, including authorship, target journals and expected dates of publication.