Trial organization
The trial has been designed by the study initiators at the Department of Radiation Oncology and the Department of Gynecology of the University of Heidelberg. The trial is carried out at the University of Heidelberg, Department of Radiation Oncology and Department of Radiation Oncology, University Medical Center Mannheim. The University of Heidelberg is responsible for trial management and coordination, as well as quality assurance including reporting, monitoring and database management.
Study design
IMRT-MC2 is a prospective, two-armed, multicenter, randomized, phase III trial. The trial workflow and treatment arms are depicted in Figure 1.
Patients fulfilling the inclusion criteria will be randomized into two arms:
Arm A- Experimental Arm
IMRT of the whole residual breast to a total dose of 50.4 Gy and 1.8 Gy per fraction with 2.3 Gy per fraction within integrated boost to the tumor bed to a total dose of 64.4 Gy in 28 fractions.
Arm B- Conventional Arm
Conventional radiotherapy of the whole residual breast to a total dose of 50.4 Gy and 1.8 Gy per fraction in 28 fractions, followed by consecutive boost to a total dose of 66.4 Gy and 2 Gy dose per fraction in 8 fractions. A total of 36 fractions is given to patients included in arm B.
Study objectives
Primary objectives of the study are cosmetic result and local control rate after radiotherapy. The cosmetic result will be evaluated at 6 weeks and 2 years post radiotherapy. Local control will be evaluated at 2 and 5 years post treatment.
Secondary objectives of the trial are quality of life at 6 weeks and 2 years after radiotherapy, as well as overall survival and disease free survival at 6 weeks, 2, 5, 10 and 15 years post radiation treatment.
Investigators
Patient treatment will be performed by radiation oncologists at the Department of Radiation Oncology at the University of Heidelberg and the Department of Radiation Oncology at the University Medical Center Mannheim.
Data Handling, Storage and Archiving
All findings including clinical and laboratory data will be documented by the investigator or an authorized member of the study team in the subject's medical record and eCRF (electronic Case Report Form). The investigator is responsible for ensuring that all sections of the eCRF are completed correctly and that entries can be verified against source data. In some cases, the eCRF, or part of the eCRF, may also serve as source documents: Karnofsky Performance Status, Documentation of Cosmetic Result and Clinical Examination.
Data will be collected and entered in a study specific database by the Study Center of the Department of Radiation Oncology at the University of Heidelberg and the Study Center of the Department of Radiation Oncology at the University Medical Center Mannheim.
All missing data or inconsistencies will be reported back to the investigators and clarified by the responsible investigator. If no further corrections are to be made in the database it will be declared closed and used for statistical analysis.
The data will be stored and archived according to §13 of the German GCP-Regulation and §28c of the German X-Ray Regulation (RöV) and §87 of the German Radiation Protection Regulation (StrlSchV) for at least 30 years after the trial termination.
Data management for this study will be coordinated by the Coordination Centre for Clinical Trials (KKS) Heidelberg.
Ethics, informed consent and safety
The final protocol was approved by the University of Heidelberg ethics committee (S-041/2009) and the Federal Office of Radiation Protection (BfS) (Z5-22461/2-2009-018). The trial is sponsored by the German Aerospace Center (DLR)/Federal Ministry of Education and Research (BMBF) of Germany (01ZP0504). This study complies with the Helsinki Declaration and its recent German version, the Medical Association code of conduct, the principles of Good Clinical Practice (GCP) and the Federal Data Protection Act. The trial will be carried out in keeping with local legal and regulatory requirements. The medical secrecy and the Federal Data Protection Act will be followed. The ClinicalTrials.gov Protocol ID is NCT01322854.
Patient selection
Inclusion criteria
Patients meeting the following criteria will be considered for admission to the trial:
Exclusion criteria
Patients presenting with one of the following criteria will not be included in the trial:
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Refusal of the patients to be included in the study
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Karnofsky Performance Score ≤70%
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Metastatic disease (M1)
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Other malignancies
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Previous radiotherapy of the breast
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Pregnancy
Study plan
502 patients (251 patients in each arm) with breast cancer and previous breast conserving surgery are included in the study according to the criteria above. Eligible patients are informed about participation in the trial with possible benefits and risks, and written informed consent is obtained. Patients are randomized into the two treatment arms after baseline photo-documentation and evaluation of the postoperative cosmetic result through an expert panel and the patient, as well as evaluation of life quality using an EORTC questionnaire.
Treatment planning and radiation therapy
Arm A
After reliable patient positioning, a thoracic CT scan with a slice distance of 3 mm is carried out. Based on the CT data set, radiation treatment planning is performed as inverse planning using the planning tool KonRad® (Siemens OCS, Erlangen, Germany). Multiple fields arranged in a star-shape around the ipsilateral hemithorax are chosen. Intensity modulation is optimized according to the specified dose directions applying an inverse treatment planning technique. 6 MV-photons are used for irradiation. IMRT can be applied either in step-and-shoot technique at a linear accelerator or at a dedicated tomotherapy unit. During treatment, regular image guidance via MV-CT is carried out for positioning control.
The clinical target volume (CTV) for the residual breast tissue and - in certain cases - the locoregional lymphatics, will be defined according to the S3 guidelines of the German Cancer Society [15]. The CTV for Arm A includes the residual breast up to 5 mm under the skin surface. The primary target volume (PTV) includes the CTV with a margin of 10 mm in all directions when optimization via virtual bolus concept is possible. In Arm A/Tomotherapy or Arm A/IMRT without virtual bolus concept the PTV will not be extended over the skin surface. The GTV includes the tumor bed, as defined by preoperative mammography.
IMRT treatment is performed in 28 fractions with 1.8 Gy per fraction to a total dose of 50.4 Gy and integrated boost with 2.3 Gy per fraction to a total dose of 64.4 Gy. This is equivalent to the dose of the conventional treatment arm in consideration of the linear-quadratic model. CTV will be covered by 45 Gy, GTV will be covered by 95% of the prescribed dose i.e. 60.8 Gy. With regard to the organs at risk, less than 10% of the heart volume may receive >30 Gy, while less than 20% of the ipsilateral lung may receive more than 20 Gy. The mean dose to the contralateral breast should be limited to less than 5 Gy.
In case dose to the target volume and dose limits to the organs at risk can not be met at the same time, compliance with the threshold dose in the target volume is paramount. However, dose limitations in contralateral structures have to be met.
Treatment duration is 53/5 weeks with 5 fractions per week.
Arm B
Patient positioning can be performed according to the standards of the participating medical centers and will be controlled weekly by conventional verification films. For treatment in Arm B thoracic scans with a slice distance of 10 mm are allowed.
The clinical target volume (CTV) includes the residual breast to the skin surface and in certain cases the locoregional lymphatics, according to the S3 guidelines of the German Cancer Society [15]. The primary target volume (PTV) includes the CTV with a medio-lateral and cranio-caudal margin of 10 mm, as well as a ventral margin of 20 mm. The GTV includes the tumor bed, as defined by preoperative mammography.
Conventional radiation treatment of the residual breast is performed in 28 fractions with 1.8 Gy per fraction to a total dose of 50.4 Gy. Subsequently, a consecutive boost to the tumor bed is carried out with 2 Gy per fraction in 8 fractions to a total dose of 66.4 Gy. Patients treated in Arm B receive a total of 36 fractions.
CTV will be covered by 45 Gy, GTV will be covered by 95% of the prescribed dose, i.e. 63.1 Gy. In regard to the organs at risk, less than 10% of the heart volume may receive >30 Gy, less than 40% of the ipsilateral lung may receive >20 Gy, while the mean dose in the contralateral breast should be less than 5 Gy.
In case dose to the target volume and dose limits to the organs at risk can not be met at the same time, compliance with the threshold dose in the target volume is paramount. However, dose limitations in contralateral structures have to be met.
Treatment duration is 71/5 weeks with 5 fractions per week.
Irradiation of the lymphatics
In both arms irradiation of the lymphatics will be performed when indicated, according to the S3 guidelines of the German Cancer Society [16].
Irradiation of the axillary lymph nodes is recommended in following cases:
Irradiation of the supra-/infraclavicular lymph nodes is recommended in following cases:
Follow up
The first radio-oncologic follow-up is planned 6 weeks after treatment completion. Further trial related follow-up visits are scheduled at 2 years and 5 years post treatment. In the time between 6 weeks and 2 years, as well as between 2 and 5 years post treatment, follow-up examinations are conducted by the attending gynecologists, according to the guidelines of the German Cancer Society.
Evaluation of the cosmetic result is conducted 6 weeks and 2 years post treatment. For complete evaluation of overall survival, disease free survival, as well as possible late side-effects, e.g. secondary cancer, a follow-up period of 15 years is necessary. Therefore, further trial related documentation will be performed at 10 and 15 years post treatment.
An overview of trial related follow-up is shown in Figure 2.
Evaluation
The cosmetic result is evaluated via photo-documentation. Before radiotherapy, 6 weeks and 2 years post treatment photographs of the patient's torso are taken in a standardized way: 2 frontal photographs from neck to midabdomen (one with arms raised and one with both arms alongside the body) and a profile photograph of the treated breast (arms raised). The pictures are evaluated by two independent investigators. Parameters to be evaluated are skin color, teleangiectasy, scars, shrinking and asymmetry. Evaluation is also carried using a quantitative digitizer scoring system, as described by Vrieling et al. [17]. Four positions are scanned on a frontal view patient photo: the mark at suprasternal notch, the mark at the midline 25 cm inferior to the suprasternal notch, the nipple position of the treated breast and the nipple position of the untreated test. These are used for the calculation of a breast retraction assessment (BRA) score. Furthermore, cosmetic evaluation is based on the standards set forth by the Harvard criteria [18]. An excellent score is given when the treated breast looks essentially the same as the contralateral, untreated breast. A good score is given for minimal but identifiable radiation effects on the treated breast, while a fair score is assigned for significant radiation effects. A poor score is used for severe sequelae of the treated breast.
Tumor manifestations within the residual breast, the regional lymphatics (axillary, parasternal, infra-/supraclavicular) or the radiation field borders are defined as locoregional relapse. Other types of tumor recurrence are considered distant metastases.
Secondary cancers must be confirmed by histological analysis. The results of the analysis should not be consistent to the original histology of the primary tumor. Date and way of diagnosis, as well as the applied dose at the site of origin of the second malignoma are documented.
Quality of life is assessed by means of the EORTC questionnaire QLQ-C30 and the breast cancer questionnaire QLQ-BR23 at 6 weeks and 2 years post treatment. The EORTC QLQ-C30 is an established instrument for measuring quality of life in cancer patients and contains 30 items that measure five functional scales, global quality of life and several cancer related symptoms. The QLQ-BR23 questionnaire is a specific tool, which contains 23 items measuring functioning and symptoms related to breast cancer [19]. Life quality assessment should include: pain/dysaestesia (yes/no), frequence/duration (no/intermittent/permanent) and treatment necessity (no/intermittent/permanent).
Statistical analysis
Primary criteria and hypotheses
Primary aim of the study is the assessment of the cosmetic outcome and local control at 2 years after breast radiotherapy. The question to be investigated is whether intensity modulated radiotherapy (IMRT) is, in spite of the reduced treatment duration, at least equivalent to conventional therapy. The combined null hypothesis (H0) is "Conventional therapy is better by more than a pre-specified margin than IMRT with respect to the cosmetic outcome or local control". The alternative hypothesis (H1) is: "IMRT is better, or worse at most by the pre-specified margin than conventional radiotherapy with respect to both cosmetic outcome and local control". The null hypothesis will be rejected, if the lower limits of both 95 per cent confidence intervals for the effect of IMRT vs. standard are higher than the respective non-inferiority margin. The non-inferiority margins are set to a relative risk of 4.67 for local control and 1.54 for the BRA measurement of cosmesis. The non-inferiority margin for local control seems very high but it is expected to correspond to an absolute risk difference of 7 percent (from 98 to 91 per cent). The adoption of local control as a primary endpoint despite low probability of loss of local control honours the importance of the endpoint and safeguards against too severe concessions in this respect. As the total radiation dose is equivalent for both arms though, it is expected that there will be no difference in local control.
Sample size calculation
The required patient number was assessed using the software R with a simulation of 9999 iterations. 251 patients per trial arm are required for a power of 97.5% with reference to cosmetic result and 82.5% with reference to local control, considering a drop-out rate of 10%. The assumed drop-out rate includes patients, who withdraw their consent to participate after randomization, as well as patients who are not treated according to the protocol, do not meet inclusion criteria or meet exclusion criteria, whose data files are incomplete or whose status is not properly assessed by follow-up examinations.
Analysis methods
Differences in the primary endpoint "cosmetic outcome" will be assessed by taking the variable as response in a linear model with the randomized treatment strategy, the age of the patients and the cosmetic parameter at baseline as explanatory variables. Local control will be estimated as the parameter for randomized treatment in a Cox proportional hazard model with age as additional explanatory variable. Approved methods for censored data, such as Kaplan-Meier estimation and/or log-rank test will be applied for statistical analysis of all secondary events.