Fatigue following radiotherapy of low-risk early breast cancer – a randomized controlled trial of intraoperative electron radiotherapy versus standard hypofractionated whole-breast radiotherapy: the COSMOPOLITAN trial (NCT03838419)

Background Fatigue is one of the most common and distressing side-effects of breast cancer radiotherapy. According to current guidelines, accelerated partial breast irradiation (APBI) may be considered as an alternative treatment option for women with early-stage low-risk breast cancer. One method for APBI is single-dose intraoperative radiotherapy (IORT) applied directly to the tumor bed during breast conserving surgery (BCS). The COSMOPOLITAN trial therefore aims to analyze the intensity of fatigue following single-shot IORT with electrons (IOERT) compared to conventional hypofractionated whole breast irradiation (WBI) in low risk early breast cancer patients. Methods This trial is conducted as a multicenter, prospective, randomized, two-arm phase II study comparing the intensity of fatigue in early-stage breast cancer (cT1cN0cM0, tumor size < 2,5 cm, ER pos. Her2neu neg., age > 50 years) treated either with WBI or APBI after BCS. Secondary outcomes investigated are tumor control, overall survival (OS), disease-free survival (DFS), acute and chronic toxicity, quality of life (QoL) and cosmesis. A total of 202 patients will be randomized into two arms: Patients in arm A will receive WBI (40.05 Gy, 15 fractions) after surgical resection, while patients in arm B will receive IOERT (21 Gy to the 90%-isodose) during BCS. Fatigue will be assessed 12 weeks post surgery with the help of the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale. Discussion The present trial aims to evaluate treatment response to compare single-shot intraoperative electron APBI to conventional WBI following BCS in early-stage low risk breast cancer patients. Fatigue is selected as the primary, patient-reported endpoint due its major clinical relevance. Trial registration The study is prospectively registered on February 12th, 2019: Clinicaltrials.gov, NCT03838419. “Intraoperative Electron Radiotherapy for Low-risk Early Breast Cancer (COSMOPOLITAN)”. Study status Ongoing study. Start of recruitment was December 2019.


Summary
Breast cancer is the most frequent malignancy in women 1, 2 . Standard therapy for early-stage breast cancer is breast conserving surgery (BCS) followed by adjuvant whole breast irradiation (WBI), which usually requires a treatment time of 3-6 weeks 1, 2 . Several randomized controlled trials (RCTs) demonstrated that postoperative WBI after BCS significantly decreased the risk of local (in-breast) recurrence and improved breast cancer mortality as well as survival 3,4 . However, one of the most common side-effects of radiotherapy is fatigue, which is reported in up to 80% of cancer patients during treatment [5][6][7][8][9][10] . Especially in early-stage breast cancer patients it might be the only serious side-effect following adjuvant irradiation, as fatigue often significantly reduces quality of life due to resulting functional impairment and psychological distress 11,12 . Fatigue additionally has a distinct socioeconomic impact: 75% of patients and 40% of caregivers are forced to change their employment status due to cancer-related fatigue 13,14 .
For reducing treatment-related toxicity, several RCTs consequently addressed the question whether adjuvant WBI could be omitted in early-stage, low risk breast cancer patients treated with endocrine therapy [15][16][17][18][19][20] . However, all these trials detected up to seven-time increased local recurrence rates without WBI following BCS [15][16][17][18][19] . Both, longer duration of radiotherapy and larger radiation field sizes are known to be associated with increase in treatment-related fatigue 21,22 .
Accelerated partial breast irradiation (APBI), delivered exclusively to the original tumor location and not to the surrounding breast tissue, might therefore be an alternative treatment option with fewer side-effects for early-stage, low risk breast cancer patients. Few previous trials have already reported comparable outcomes for highly selected low-risk breast cancer patients for APBI compared to conventional WBI [23][24][25][26] . First results also point out that APBI compared to WBI might be associated with less severity and intensity of fatigue 22,27,28 .
One method for APBI is single-dose intraoperative radiotherapy (IORT) delivered directly to the tumor after resection. APBI with electron IORT might even contribute to further reducing treatment-related fatigue, as duration of adjuvant radiotherapy is dramatically shortened to one day compared to 3-5 weeks for conventional WBI. Data is still limited for APBI, hence current international and German guidelines suggest the use of APBI for low-risk early stage breast cancer patients but recommend the application of APBI preferably within a clinical trial 1, 2, 29 .
The present trial therefore aims to evaluate treatment response to intraoperative electron APBI compared to conventional WBI following BCS in early-stage low risk breast cancer patients. The primarily investigated endpoint is the intensity of fatigue, as objectively assessed with the help of the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale at 12 weeks after treatment start. Secondary endpoints include local, regional and distant tumor control, diseasefree and overall survival, quality of life, cosmesis and toxicity. Additionally, the Prosigna/PAM50assay will be used to further evaluate the potential prognostic impact of tumor biology and gene expression-analysis in supporting adequate patient selection for APBI.
The ultimate form of APBI is single-dose intraoperative radiotherapy (IORT) delivered to the tumor A meta-analysis of 5 RCTs comparing APBI to WBI was conducted by the TARGIT A-investigators 36 .
While breast cancer-related mortality was similar, APBI resulted in a significant decrease of nonbreast cancer-related mortality and a borderline significant improvement in overall survival when using a random-effects model 36 . Based on the above mentioned studies, both national guidelines in Germany, but also international guidelines suggest the use of APBI in patients with early stage, Another study observed substantial variability in Ki67 scoring even among some of the world's most experienced laboratories 39 .
On the contrary, for facilitating the decision about the need for adjuvant chemotherapy besides endocrine treatment, current guidelines support the application of multi-gene testing for patients with early-stage hormone-receptor positive, HER2-as well as node-negative breast cancer 1, 2, 40, 41 .
By using these multi-gene assays, early stage low risk breast cancer patients with a 10-year distant recurrence rate of less than 10% can be identified, who have minimal if any benefit from additional chemotherapy added to regular endocrine treatment 38,[40][41][42][43] . One of the current, wellestablished multi-gene assays is the PAM50-based Prosigna risk of recurrence (ROR) (NanoString Technologies) test, which has been shown to have a high prognostic relevance and was therefore approved for selecting early-stage low risk patients for whom chemotherapy and extended endocrine therapy might not be indicated 44 . As these biological markers support the classification of early-stage breast cancer patients into groups that are associated with a good or a poor prognosis, they might also be helpful for more precisely identifying early stage low risk breast cancer patients for whom APBI is sufficient instead of WBI. A recent retrospective analysis of the ABCSG-8 trial analyzing 1,308 postmenopausal endocrine responsive breast cancer patients even underlined the prognostic impact of the PAM50-assay in predicting local recurrence 45,46 .
Fatigue is one of the most common and distressing side-effects reported by breast cancer patients and occurs in more than 80% of patients during radiotherapy [5][6][7][8][9][10] . During the course of radiotherapy, fatigue usually increases, but typically subsides within weeks after the end of radiation treatment 7, 12 . However, in up to 40% of cases, it can persist long after the completion of therapy [47][48][49] . Fatigue is usually described as a general physical or mental exhaustion that negatively affects quality of life due to functional disability and psychological distress 11,12 .
Psychosocial problems like fatigue, depression or cognitive limitations in occupationally active cancer survivors are distinctly associated with problems at work 50 . The potential economic impact of fatigue is considerably high: 75% of patients and 40% of caregivers are forced to change their employment status due to cancer-related fatigue 13,14 . A recent study about employment participation in early-breast cancer patients further highlighted the enormous socioeconomic impact of fatigue by showing that fatigue patients were more likely to experience diminished employment after 2 years of follow-up 51 .
Previous analyses reported that the level of fatigue rises with cumulative radiation dose and might be related to the duration of treatment 21,52 . Both, total dose as well as field sizes are known to influence severity of fatigue 21,22,53 . For APBI the target volume only includes the former tumor cavity and not the whole breast tissue and total treatment time is usually reduced compared to WBI, hence early stage breast cancer patients treated with APBI instead of WBI are expected to recover faster from cancer-related fatigue leading to improved quality of life compared to patients receiving WBI.
Indeed, few first and mainly retrospective studies with small patient numbers reported lower levels of acute fatigue in breast cancer patients receiving APBI instead of WBI 22,27,28 . Furthermore, the GEC-ESTRO study group recently investigated quality of life following APBI with interstitial brachytherapy and described significantly reduced fatigue after APBI compared to WBI 54 .
The aim of the present trial is to compare single-shot intraoperative APBI with electrons to standard hypofractionated WBI for patients with low-risk early stage breast cancer. Due to its high socio-economic and clinical impact fatigue is chosen as the primary, patient-reported endpoint for this study. The Prosigna/PAM50-assay will be applied to further evaluate the potential prognostic impact of tumor biology and gene expression-analysis in supporting adequate patient selection.

Trial Rationale/ Justification
The primary goal of this trial is to show that BCS followed by APBI with electrons results in a significantly better tolerability of adjuvant radiotherapy in terms of fatigue compared to BCS followed by hypofractionated WBRT. Fatigue is a major side effect of cancer treatments and is a main contributor to long-term quality of life-impairment as well as unemployment 11,13,14,51 . The prognosis of women with early stage, low risk breast cancer is excellent and the risk of local recurrence after BCS has been shown to be in the range of 1-2% at 5 years after diagnosis 20 . Thus, maintaining a high quality of life and minimizing morbidity and mortality of adjuvant treatment is crucial. There exists strong and prospective data supporting the hypothesis that APBI for early-stage lowrisk breast cancer patients is non-inferior to WBI, the current standard of care for those patients, and that therapy-associated toxicity can even be reduced [23][24][25][26] . Those findings have already been incorporated within the respective NCCN and German guidelines 1, 2, 29 . As data regarding local control and survival following APBI is still limited to results after 5-10 years of follow-up, patients are encouraged to participate in a clinical trial 1, 2, 29 . The above mentioned and discussed ELIOT trial applied intraoperative electron radiotherapy for APBI and reported to WBI comparable local recurrence rates after excluding patients with high-risk factors in the IORT arm 58 . The American

Benefit/ Risk Assessment
Society for Therapeutic Radiology and Oncology (ASTRO) has therefore published selection criteria for APBI which were adapted by the current NCCN guideline 37 . The ASTRO criteria will be applied for guaranteeing that only low-risk early-breast cancer patients will be treated with APBI in the current trial.
By participating in this trial, early-stage low-risk breast cancer patients have the chance to be treated with intraoperative electron APBI, an established form of treatment, which is expected to

Trial Objectives
The purpose of this trial is to analyze intensity of fatigue in early-stage breast cancer treated with WBI or APBI after BCS. We propose that patients treated with APBI have lower fatigue levels after radiotherapy based on the FACIT Fatigue Assessment Questionnaire compared with patients treated with standard WBI.

Primary Objective
The primary objective is the assessment of fatigue from baseline (before treatment start) compared to 12 weeks after treatment start as assessed by the FACIT Fatigue Assessment Questionnaire.

Explorative Objectives
Gene expression analysis using the Prosigna/PAM50-assay to evaluate the potential prognostic/predictive impact on choice of radiotherapy modality

Trial Design
This trial will be conducted as a prospective, randomized, two-arm Phase II study.

Trial Duration
The overall duration of the trial is expected to be approximately 84 months. Recruitment of patients will start in January 2019. Recruitment of the patients is planned over a time period of 24 months, minimum duration of the follow-up phase will be 5 years.
Total trial duration: 84 months

General Criteria for Patients' Selection
Women with early stage, low risk breast cancer eligible for breast-conserving surgery will be evaluated and screened based on the protocol. All patients fulfilling the inclusion and exclusion criteria will be informed about the possibility to participate in the study. Registration for the study must be performed prior to beginning of RT.

Inclusion Criteria
Women with early stage, low risk breast cancer eligible for breast-conserving surgery meeting all of the following criteria will be considered for admission to the trial:

Exclusion Criteria
Patients presenting with any of the following criteria will not be included in the trial:

Withdrawal of Patients
A subject may voluntarily discontinue participation in this study at any time at their own request or at request of the legal representative. In addition, study treatment will be discontinued if unmanageable toxicity is documented, or if the Principal Investigator makes a decision to terminate the study. A subject will be withdrawn from the protocol if, in the investigator's opinion, continuation of the trial would be detrimental to the subject's well-being. If the subject withdraws from the trial and also withdraws consent for disclosure of future information, no further evaluations should be performed, and no additional data should be collected. The PI may retain and continue to use any data collected before such withdrawal of consent, in case the patient has not withdrawn the further use of his data as well.

Handling of Withdrawals
In all cases, the reason for withdrawal must be recorded in the Case Report Form and in the subject's medical records. In case of withdrawal of a subject at his/ her own request, the reason can be asked and documented. All efforts will be made to follow up the subjects and, all examinations scheduled for the final trial day will be performed as far as possible on all patients and documented. All ongoing Adverse Events (AEs)/ Serious Adverse Events (SAEs) of withdrawn patients have to be followed up until no more signs and symptoms are verifiable or the subject is on stable condition.

Replacement of Patients
Patients will not be replaced if consent is withdrawn retrospectively and patients have already been randomized.

Premature withdrawal of patients from the study
Individual termination criteria during the treatment phase: Individual termination criteria during the follow-up phase:  at any time at the request of the patient

Premature end of trial/ Withdrawal of the whole study
Reasons for premature termination of the entire study are:

Prior and Concomitant Illnesses
Relevant additional illnesses present at the time of informed consent are regarded as concomitant illnesses and will be documented in the patient chart. Abnormalities which appear for the first time or worsen (intensity, frequency) during the trial are adverse events (AEs) and must be documented on the appropriate pages of the CRF. for hormone therapy is allowed during the treatment period in this trial.

Treatment Planning for APBI and dose prescription
Patients will receive electron IORT with a total dose of 21 Gy prescribed to the 90%-isodose.
Selection of the appropriate size and shape of the tube is at the discretion of the treating physician, but a minimum diameter of 1-2 cm in addition of the clinical tumor size is suggested.
The tumor bed should be prepared according to the instructions by Veronesi et al 58 . A lead or aluminum shield shall be inserted on the surface of the major pectoralis muscle to protect the thoracic wall. The linear accelerator delivers electrons at variable energies (6,9 and 12 MeV).
Depending on the target thickness the adequate electron energy is chosen.

Treatment Planning for whole breast irradiation and dose prescription
Radiotherapy is administered after full recovery from surgical resection, usually after 5 weeks of BCS. Patients will receive computed tomography-based 3-dimensional treatment planning. The total dose to the breast is 40.05 Gy in 15 fractions. The use of intensity-modulated radiotherapy and deep inspiration breath hold techniques is permitted. No tumor bed boost or regional nodal irradiation shall be delivered.
Target contouring of the CTV-breast is performed according to the ESTRO-guidelines 59,60 . An additional margin for inter-and intrafractional positioning uncertainties of 5-10 mm is added to generate the PTV-breast. The PTV-breast_EVAL (generated by subtraction of the 3 mm below the skin from the PTV-breast) should receive 95%-107% of the prescribed dose.

Randomization
After initiation of the study, patients will consecutively be screened and eligible patients will be enrolled into the study. To achieve comparable intervention groups, patients will be allocated in a concealed fashion in a 1:1 ratio by means of randomisation using a centralised web-based tool (www.randomizer.at). Randomization will be stratified with respect to invasive tumor size (≤ 1 cm³, > 1 cm³) and age (≤ 60 years, > 60 years). Block randomisation with varying block lengths will be performed to achieve in total equal group sizes.

Study visits
After screening of patients for inclusion and exclusion criteria and having received informed consent, appropriate patients will be recruited to the trial. Study relevant data will be collected and patient history will be assessed. Patients will be randomized 1:1 to one of the two study arms. The baseline visit (T0) will be scheduled -7 to -1 day before planned treatment start. Both groups will be evaluated after BCS at 5 weeks after treatment start (Study Visit 1), to assess to potential influence of IORT on fatigue (secondary endpoint). In group A this time point corresponds to 5 weeks after BCS, just before the start of RT; in group B this corresponds to 5 weeks after BCS incl. IORT.
After the first study visit patients will receive regular follow-up visits based on the standard follow-up program of current German guidelines 1, 2 . The second, third, fourth and fifth study visits are planned 12 weeks (primary endpoint), 6 months, 2 and 5 years (secondary endpoints) after the treatment start. These visits will include a clinical assessment as well as analysis of quality of life including fatigue (EORTC and Fatigue Assessment Questionnaires, BREAST-Q and BCTOS, see below for details). Photographic assessment of cosmetic results is also planned except for the last visit after 5 years. The last subject in (LSI) will be followed 5 years after baseline. This is considered the final study visit. -Screening -Screening for the study will be performed prior to inclusion of the patient into the study. All inclusion and exclusion criteria must be fulfilled.
-Baseline Visit (T0) Baseline Visit will be performed after inclusion of the patient into the study protocol. The baseline visit will be scheduled -7 to -1 day before planned treatment start/BCS.
The following examinations will be performed: -Clinical assessment using CRF The first study visit is scheduled 5 weeks (+/-2 week) after treatment start in both groups. As group B receives irradiation with intraoperative electron radiotherapy, this visit will also take place 5 weeks after RT for group B.
The following examinations will be performed: -Clinical assessment using CRF The second study visit is planned 12 weeks (+/-2 week) after treatment start for both groups. For group A, this is 7 weeks after hypofractionated WBI, while for group B this visit is 12 weeks after IORT.
The following examinations will be performed: -Clinical assessment using CRF The third study visit is scheduled 6 months (+/-2 weeks) after treatment start. The following examinations will be performed: -Clinical assessment using CRF The fifth study visit is scheduled 5 years (+/-3 months) after BCS. The following examinations will be performed: -Clinical assessment using CRF

Trial Methods
The primary objective is to compare change on the overall fatigue scale from baseline (before surgery) to week 12 after treatment start between breast cancer patients treated with hypofractionated WBI or intraoperative APBI. Secondary analysis include local tumor control, regional and distant recurrence rates, disease-free as well as overall survival, assessment of acute and chronic toxicity, quality of life and cosmesis. Furthermore, gene expression analysis using the Prosigna/PAM50-assay will be performed as a secondary endpoint to evaluate the potential prognostic/predictive impact on choice of radiotherapy modality.

Primary endpoint: Fatigue Testing
The primary endpoint is change of fatigue after APBI or WBI from baseline to 12 weeks after treatment start (T2 vs. T0). Fatigue will be assessed with the help of the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, which consists of a 13-item multidimensional selfassessment form evaluating quantity of fatigue and distress 61 . The FACIT Fatigue Scale is extensively applied in cancer patients 27,62 . Using the FACIT Fatigue Scale questionnaire, patients are asked to indicate how frequent each item was for them "during the past 7 days" applying a 5point scale ("not at all" to "very much"). The range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.

Secondary endpoints
Time to progression is defined as the number of days from randomization to the first occurrence of the respective event. the end of the study, the local control time will be censored at the time of the last study visit.

Regional tumor control
Regional tumor control is regarded as no occurrence of regional lymph node metastases (axilla, supraclavicular fossa, internal mammary chain). Regional tumor control is defined as number of days from randomization until occurrence of regional lymph node metastases, death without prior regional tumor progression, or end of follow-up. For patients alive and not diagnosed with regional progression at the end of the study, the regional tumor control time will be censored at the time of the last study visit.

Distant tumor control
Distant tumor control is defined as no occurrence of distant metastases (lymph node metastases in the axilla, supraclavicular fossa and internal mammary chain are not classified as distant metastases, see above). Distant tumor control is defined as number of days from randomization until occurrence of distant metastases, death without prior distant progression, or end of followup. For patients alive and not diagnosed with distant progression at the end of the study, the distant tumor control time will be censored at the time of the last study visit.

Overall survival
Overall survival time, defined as number of days from randomization until death or end of followup. For patients alive at the end of the study, the overall survival time will be censored at the time of the last visit or follow-up contact.

Disease-free survival
Disease-free survival, defined as number of days from randomization until the first occurrence of local recurrence, regional lymph node metastases, distant metastases, tumor-related death, death without prior progression, or end of follow-up. For patients alive and not diagnosed with progression at the end of the study, the disease-free survival time will be censored at the time the patient was last known to be free of progression of tumor disease.

Secondary malignancies
The frequency of secondary malignancies as well as the time of their diagnosis will be assessed during follow-up visits.

Toxicity/ quality of life
Detailed acute and chronic potentially therapy-related toxicity will be assessed during each

Cosmesis
Photographic assessments before and after BCS will be taken at baseline, during the first, the second and the forth study visit (T0, T1, T2, T4). Evaluation of breast cosmesis will be performed according to the proposed method by Vrieling et al 68 .
Two frontal views of the chest will be taken, one with hands near the body and the other with hands raised as far as possible above the head. A profile view of the treated breast (arms above the head) is also planned for each assessment. The suprasternal notch as well as a point 25 cm below in the midline will be marked. Quantitative analysis is performed by a panel of doctors according to the graphic below. The three components of the indices (breast retraction assessment (BRA), percentage BRA (pBRA), reference length (Ref)) are determined as shown below and the resulting values are calculated: Illustration of the measurements according to Vrieling et al. 68

Gene expression analysis using the Prosigna/PAM50-assay
The Prosigna/PAM50-assay will be applied on the operatively resected tumor tissue according to manufactor's instructions 69 .

Plan for Treatment or Care after the Trial
After completion of study treatment, any standard treatment may be considered. Any systemic treatment or chemotherapy is not part of the clinical trial. For tumor progression, treatment alternatives will be evaluated and discussed interdisciplinary considering options of surgical resection, systemic therapy (chemotherapy, molecular targeted therapies, immunotherapy) as well as re-irradiation in certain cases.

Assessment of Safety
During and following a subject's participation in the trial, the investigator should ensure that adequate medical care is provided to a subject for any adverse. The investigator should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware. RT will be carried out as ambulatory treatment; however admission to the ward for supportive care is possible when necessary. Supportive measures include skin care, pain management will be performed at the discretion of the treating radiation oncologist.

Adverse Events
Toxicity associated to irradiation that occurs for the first time after treatment start or preexisting toxicity that significantly increases in the severity grade after the start of study treatment likely to be related to radiotherapy will be documented within the subject's medical records and eCRF.
Treatment related side effects will be recorded according to CTCAE v5.0 (Common Terminology Criteria for Adverse Events version 5.0; http://www.eortc.be/services/doc/ctc). Grades refer to the severity of the adverse event.
Acute toxicities are defined by the occurrence within the first 90 days after the start of RT.
Adverse Events occurring after the first 90 days until 6 months after study treatment will be documented as subacute toxicities. Any adverse event emerging more than 6 months after RT will be recorded as late toxicities.
Standardized informed consent forms for irradiation of breast cancers are utilized to inform the patient about study treatment. Expected acute side effects of RT include radiation dermatitis, fatigue, pain, soreness and dryness of the breast, pruritus of the skin, hairloss in the axilla, sore throat and change in breast size, shape and color. Characteristics and severity of subacute/ late side effects depend on the location and the extent of the target volume/ irradiation field and include skin fibrosis, change in breast size, shape and color, lymphoedema, lung fibrosis, rib fractures, cardiac disorders like cardiac arrhythmia, cardiac insufficiency and coronary heart disease, soft tissue necrosis as well as brachial plexopathy.
Acute/ subacute toxicities will be assessed prior, during and after RT, including: -Skin disorders: radiation dermatitis, dryness and pruritus of the skin, hairloss in the axilla, lymphedema

Serious Adverse Events
A serious adverse event is an adverse event with a special degree of severity in that it  leads to death (CTCAE grade 5)  is life-threatening (CTCAE grade 4) due to its actual and documented severity at the point of occurrence (not only life-threatening in principle if occurrence was more severe)  causes or prolongs hospitalization  is a congenital anomaly/ birth defect  leads to a lasting or otherwise significant impairment  is an otherwise significant medical incident The following examples are not to be considered SAE:  Medical or surgical interventions  Hospital admissions that are not the consequence of a medical condition (e. g. social/ convenience admissions)  day-to-day fluctuations of pre-existing illness(es) or toxicity present or detected at the start of the study that do not worsen  A planned hospitalization where admission did not take longer than anticipated  Tumor progression and all medical intervention performed to offer respective therapy or relieve the symptoms of such progression

Sample Size Calculation
The sample size calculation is based on the primary endpoint change of fatigue from baseline to week 12 after Treatment start (study visit T2 ) between the groups APBI and WBI measured via the FACT-Fatigue score. An improvement in 6 of 13 items by one point is considered clinically relevant resulting in a clinically relevant effect size of 6 points. Assuming a standard deviation of 12 70 and with a type I error rate of (two-sided), a two sample t-test requires a total sample size of n=172 patients (86 per group) to achieve a power of for revealing an effect of 6 points. Adjusting for the covariates baseline fatigue, age, and tumor size in a linear model is assumed to yield less unexplained variance and thus to an additionally increased power. Taking a dropout rate of 15% percent into account, n=202 patients need to be randomized. Sample size calculation was carried out using ADDPLAN v 6.1.

Analysis sets
The full analysis set (FAS) includes all randomized patients and they will be analyzed according to the treatment they were randomized to.
The per-protocol population (PP) is a subset of the FAS set and compromises all patients, who were treated according to the randomized treatment as outlined in the protocol without major protocol violations.
The safety population will consist of all patients who received one of the study treatments at least once, and patients will be allocated to the treatment they actually received. This will be the primary analysis set for the safety analysis.
Each patient's allocation to the different analysis will be defined prior to the analysis. The allocation will be documented in the statistical analysis plan. During the data review, deviations from the protocol will be assessed as "minor" or "major". Major deviations from the protocol will lead to the exclusion of a patient from the PP analysis set.

Confirmatory analysis
The null hypothesis to be tested states that the change in the FACT-F score between baseline and week 12 after treatment start is equal for both groups: This hypothesis will be tested at a two-sided level of significance of 0.05 against the alternative hypothesis: The hypothesis test will be conducted using a linear model with the dependent variable "change in FACT-F score between baseline and week 12 after treatment start" and the independent factors treatment group (A/B), baseline FACT-F score, tumor size, and age. The effect estimate for the treatment group will be calculated alongside a 95% confidence interval.
The confirmatory analysis will be primarily based on the FAS which is consistent with the intention-to-treat (ITT) principle by including all patients who were randomized to the two groups.
Missing data for the primary outcome variable will be replaced using multiple imputation 71 taking the covariates treatment group, baseline FACT-F score, tumor size, and age into account by application of the fully conditional specification method 72 . This will be realized using the option "FCS" of the SAS "MI" procedure which is implemented in SAS 9.4. M=10 imputations will be done and the regression approach will be used to impute the data.

Further analyses
In addition to the evaluation of the FAS, a PP analysis will be performed as a sensitivity analysis.
The secondary outcomes will be analyzed descriptively by tabulation of the measures of the empirical distributions. According to the scale level of the variables, means, standard deviations, medians, 1 st and 3 rd quartiles as well as minimum and maximum or absolute and relative frequencies, respectively, will be reported. Further, for the secondary endpoints overall survival (OS), disease-free survival (DFS), local, regional, and distant tumor control, a Kaplan-Meier analysis will be performed and a between-groups comparison via a descriptive log-rank test will be conducted. Adverse and Serious Adverse Events will be tabulated and absolute and relative frequencies with 95% confidence intervals will be calculated. The severity and the relationship to the treatment will be given. Possible differences between the treatment groups will be tested using the chi-squared test. Descriptive p-values of the corresponding statistical tests comparing the treatment groups and associated 95% confidence intervals will be given. Further exploratory analyses will be performed to identify subgroups and potential moderator variables of patients profiting distinctly from the investigated interventions. Analyses will be conducted using SAS v9.4 (SAS Institute, Cary, NC)

SOP (Standard operating procedures)
All participating investigators are guided by the study-specific SOPs that are provided by the study administration.

Data quality
To After each internal monitoring, the principal investigator receives a monitoring report. This is kept in the Investigator site file (ISF).

Data management
The data is collected, managed and processed electronically in the in-house HIRO research database. It is the responsibility of the principal investigator to conduct the study in accordance with applicable legal provisions and the study protocol, and that the data is entered correctly and completely in the eCRFs. All data collected in this study must be documented by authorized persons in the eCRFs. Access to the database must be authorized in writing by the principal investigator (Signature Log). Access authorization may not be passed to third parties.
Data in the HIRO database will be checked by programmed value ranges, validity and consistency checks. If necessary, queries may arise that are made using the HIRO database and authorized persons. Based on the queries, the study physician / study nurse can review and answer or correct the resulting discrepancies.
After completion of the study and after entry of all relevant data and clarification of the queries, the data base will be closed. The originals of all central study documents, including documentation sheets, are kept at the Study Center for at least 15 years after the final report has been prepared.

Patient identification list
Study participation is recorded by registering the patient within the study cockpit ("Studiencockpit") of the clinic's hospital information system in an electronic patient identification list. It is used exclusively by the study personnel for the subsequent identification of the participating patients. This list is kept absolutely confidential and archived for at least 15 years after the end of the study. In addition, the patient's participation in this clinical trial is marked in the patient record.

Investigator Site File (ISF)
The Investigator Site File stores the documents required for the clinical study. The principal investigator is responsible for keeping the ISF up to date and complete. After completion or termination of the study, it must be kept for at least 15 years.

Data storage
The originals of all central study documents, including CRFs, are kept in the study center for at least 15 years after the final report has been prepared. The principal investigator keeps the administrative documents (correspondence with the ethics committee, study administration, study center), the patient identification list, the signed informed consent forms, copies of the CRFs and the general study documentation (protocol, amendments) for the above mentioned time. Original data of study patients (medical records) must be kept for at least 15 years.

Final Report
All information pertaining to this clinical trial should be treated confidentially. The statistical analysis and the preparation of a final report will be realized and signed by the principal investigator, the study coordinator and biometrician within 12 months after the closure of the database. All information contained in this report is strictly confidential.

Publications
For the international publication of the study results, this study protocol was registered in the database of the National Institute of Health (www.clinicaltrials.gov) or in the German Register of Clinical Trials (DRKS) (https://www.drks.de/drks_web/).
The results of this clinical study will be published under the responsibility of the principal investigator. The first and last authorship are reserved for the principal investigator and the study coordinator of the study if both do not wish to transfer their authorship to a third person. All information about the study must be kept confidential until then. The final publication is planned after the end of the study. The presentation of the results in the context of a publication is based on existing requirements for publications.

Responsibilities of the Principal Investigator
The principal investigator is responsible for initiating, organizing and funding the clinical trial.

Ethics committee, DEGRO expert committee
Study protocol, patient information and the informed consent form are submitted to the ethics committee of the Medical Faculty of the University of Heidelberg for professional counseling. The study will start only after receiving the approval. The Ethics Committee will be promptly informed by the principal investigator of any changes in the study protocol that may affect patient safety.
In the clinical study, no ionizing radiation in humans for the purpose of medical research according to §23 StrlSchV is used, since all treatments within this protocol are clinically indicated and performed within the medical responsibility of the participating centers. An application to the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS) is therefore not required. The study was submitted to the DEGRO expert committee for advice. Recruitment will not start before the committee classifies the protocol as a medical science ("Heilkunde").

Patient information and informed consent
After informing the patient-in oral and written form -of the nature, significance, implications, expected benefits and potential risks of the clinical trial, each patient must provide written informed consent to participate in the study before enrollment. The patient must be provided with sufficient time and opportunity to decide on her participation prior to the initiation of any study measures and to be able to clarify open questions with the attending physician. The informed consent form includes the date and signature of the participant and the study physician. A copy of the informed consent form and the patient information will be handed out to the participant, the original will be placed in the Investigator Site File.
Furthermore, the patient has the option to decide separately on the transfer of his data to third parties, a refusal has no effect on study participation and on the further use of his data outside the aims of this study (e.g. meta-analyses).
The study participant can withdraw the consent at any time and without stating reasons. The study participant is asked to give the reason for withdrawal, but it is pointed out that she does not have to do this. The information about the withdrawal must be documented in the patient file as well as on the participant's informed consent form. On request, a copy of the correspondingly amended informed consent form will be handed out. The treating physician/ study nurse must ensure that the revocation of consent is communicated to the data management. The datasets will remain on the in-house HIRO database and may continue to be used for scientific studies. In the case of consent withdrawel, the data may continue to be used, as long as there is no request for the complete deletion of the data.

Patient insurance
Since only clinically established therapies and diagnostics are used within the study, there is no study-specific insurance. As for treatments outside of studies, this means that study participants are not insured for the health damage or other adverse effects that they might experience in connection with participation in this study at the University Hospital Heidelberg, unless the physician or his staff meets culpable misconduct. Intent and negligence are to be regarded as culpable misconduct.
The study participants are not accident insured on the way to and from, as well as during an outpatient irradiation, with the exception of study-related appointments (i.e. TO in group A (baseline visit)).

Data Protection and medical confidentiality
The names of the patients and all other confidential information are subject to medical confidentiality and the provisions of the General Data Protection Regulation (DSGVO) as well as "Landesdatenschutzgesetz" and "Bundesdatenschutzgesetz" (LDSG or BDSG). Patient data will only be shared in pseudonymised form. Third parties do not get any insight into original documents. The prerequisite for this is the voluntary approval of the study participants in informed consent form. For this, the study participants are informed about the following: 1. Personal data collected in the context of this clinical study, in particular health and ethnic information, will be recorded in paper form and electronic in care report files (CRFs) at the radiotherapy clinic.

Authorized and confidential staff of the Department of Radiation Oncology and
Radiotherapy, University Hospital Heidelberg can view personal data for monitoring. To ensure the quality of the study, the data may be transferred in pseudonymised form to authorized representatives of the leading study center. For this measure, the study physician is released from his medical confidentiality.
3. The collected data, including imaging material, will be exported in pseudonymised form for scientific research purposes in the field of cancer research in collaboration with other institutions (possibly with private companies or partners abroad with possibly lower data protection levels). For research purposes, the pseudonymised data may be linked to other data from other sources (such as diagnostic records, treatment planning, cancer registry, medical records, etc.).
4. The consent can be withdrawn by the patient at any time, without giving reasons and without disadvantages for further medical care. In the case of such a revocation of the consent, the data may continue to be used, as long as there is no request for the complete deletion of the data.
5. Health data of the study participant can be collected or viewed by co-treating physicians as necessary for the proper conduct and monitoring of the study. In that regard, physicians are released from confidentiality.
6. The study participant may allow that his or her family physician / other treating physicians are informed about his or her participation in the study and may be asked for further information as part of the follow-up.

Funding
The trial is financed using funds of the Department of Radiation Oncology at the University Hospital of Heidelberg. According to the research agreement of our clinic with IntraOP Medical, this trial is financially supported IntraOP Medical, 570 Del Rey Avenue, Sunnyvale, CA 94085.
IntraOP Medical is not involved in the design of the study, nor the collection/storage/analysis of the data gathered in this study. All persons involved (including the principal investigator and coinvestigators) declare that there is no conflict of interest in connection with the implementation and evaluation of this study.

Amendments
In the interests of sound data analysis, changes in the study protocol are not scheduled. In exceptional cases, however, changes to the study conditions are possible. Any change to the study procedure must be made in writing, stating the reasons, and signed by all persons responsible for the study. The changes will then be considered part of the study protocol. If required (e.g., dose changes of the radiation and / or other significant changes that directly affect the safety of the study participants), the approval of the responsible ethics committees and the study participant must be obtained. Changes or additions to the study protocol can only be initiated and authorized by the principal investigator.

Signatures
The present trial protocol was subject to critical review and has been approved in the present version by the persons undersigned. The information contained is consistent with: -the current risk-benefit assessment of the investigational treatment -the moral, ethical, and scientific principles governing clinical research as set out the principles of GCP and in the applicable version of Declaration of Helsinki. The investigator will be supplied with details of any significant or new finding including AEs relating to treatment with the investigational treatment.