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Breast Neoplasms

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Breast Carcinoma In Situ

Carcinoma, Intraductal, Noninfiltrating

Carcinoma, Ductal, Breast

Breast Diseases

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Estrogens

Progesterone

Standard fractionation whole breast irradiation (WBI) with sequential boost.

Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost

Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery.

Standard fractionation whole breast irradiation

Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery.

Hypofractionated whole breast irradiation

15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.

Concurrent boost

6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.

Sequential boost

Frank A. Vicini, MD, FACR

Gary M. Freedman, MD

Julia R. White, MD

Douglas W. Arthur, MD

RATIONALE: It is not yet know whether higher per daily radiation therapy is equally as effective as standard per daily radiation therapy in treating breast cancer.

PURPOSE: This randomized phase III trial studies how well an accelerated course of higher per daily radiation therapy with concomitant boost works compared to standard per daily radiation therapy with a sequential boost in treating patients with early-stage breast cancer that was removed by surgery.

OBJECTIVES:

Primary

* To determine whether an accelerated course of hypofractionated whole-breast irradiation (WBI) including a concomitant boost to the tumor bed in 15 fractions following lumpectomy will prove to be non-inferior in local control to a regimen of standard WBI with a sequential boost following lumpectomy for early-stage breast cancer patients.

Secondary

* To determine whether breast-related symptoms and cosmesis from accelerated WBI that is hypofractionated (in only 3 weeks) with a concomitant boost is non-inferior to standard WBI with sequential boost.
* To determine whether the risk of late cardiac toxicity in patients with left-sided breast cancer treated with hypofractionation will be non-inferior to conventional fractionated radiation therapy (RT) based upon analysis of radiation dosimetry from CT-based treatment planning and normal tissue complication probability (NTCP) calculations.
* To determine whether CT-based conformal methods intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for WBI are feasible in a multi-institutional setting following lumpectomy in early-stage breast cancer patients and whether dose-volume analyses can be established to assess treatment adequacy and likelihood of toxicity.
* To determine that cosmetic results and breast-related symptoms 3 years after hypofractionated breast radiation with concomitant boost will not be inferior to that obtained 3 years after WBI with sequential boost.
* To determine whether future correlative studies can identify individual gene expressions and biological host factors associated with toxicity and/or local recurrence from standard and hypofractionated WBI.
* If shown to be non-inferior, to then determine if accelerated course of hypofractionated WBI including a concomitant boost to the tumor bed in 15 fractions following lumpectomy will prove to be superior in local control to a regimen of standard WBI with a sequential boost following lumpectomy for early-stage breast cancer patients.
* To determine whether treatment costs for hypofractionated WBI with concomitant boost are not higher than WBI with sequential boost.

OUTLINE: This is a multicenter study. Patients are stratified according to age (\< 50 vs. ≥ 50 years), prior chemotherapy (yes vs. no), estrogen-receptor status (+ vs. -), and histology grade (1-2 vs. 3). Patients are randomized to 1 of 2 treatment arms. Treatment begins within 9 weeks of last surgery or chemotherapy delivery.

After completion of study therapy, patients are followed at 1 month, at 6 months, and then yearly.

Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery

A Phase III Trial of Accelerated Whole Breast Irradiation With Hypofractionation Plus Concurrent Boost Versus Standard Whole Breast Irradiation Plus Sequential Boost for Early-Stage Breast Cancer

In-breast recurrence (IBR) is defined as any of the following: invasive local recurrence-ipsilateral breast (within treatment field); invasive local recurrence-ipsilateral breast (outside treatment field); non-invasive local recurrence-ipsilateral breast (within treatment field); or non-invasive local recurrence-ipsilateral breast (outside treatment field). Time to IBR is defined as time from randomization to the date of first IBR, last known follow-up (censored), or death without IBR (competing risk). IBR rates are estimated using the cumulative incidence method, while treatment effect comparisons are based on cause-specific hazards. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. 5-year rates are provided.

Failure is defined as death due to any cause. Failure time (overall survival time) is defined as the time from randomization to the date of death or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method and distributions between the two arms are compared using the log-rank test. Five-year rates are provided here.

Disease-free survival (DFS) time is defined as time from randomization to local-regional disease recurrence, distant metastases, second/new primary, death due to any cause or last known follow-up (censored). DFS rates are estimated by the Kaplan-Meier method and distributions between the two arms are compared using the log-rank test. Five-year rates are provided here.

Distant disease-free survival (DDFS) time is defined as time from randomization to distant metastases, second/new primary, death due to any cause or last known follow-up (censored). DDFS rates are estimated by the Kaplan-Meier method and distributions between the two arms are compared using the log-rank test. Five-year rates are provided here.

Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data

The BCTOS cosmesis subscale score measures perceived aesthetic (e.g., breast shape) status . Patients rated each item using a four-point scale evaluating the differences between the treated and the untreated breast (1=no difference, 2=slight difference, 3=moderate difference, 4=large difference) with higher scores indicating a worse outcome. The score for each subscale is the mean of the ratings over all items belonging to that specific subscale. Change was calculated as the value at 3 years minus the value at baseline. A positive change reflects a decline at 3 years and a negative change reflects an improvement at 3 years.

Physicians rated cosmesis using a four point scale:

* Excellent: When compared to the untreated breast or the original appearance of the breast, there is minimal/no difference in the size or shape of the treated breast.
* Good: There is a slight difference in the size or shape of the treated breast as compared to the opposite breast or the original appearance of the treated breast.
* Fair: Obvious differences in the size and shape of the treated breast. This change involves quarter or less of the breast.
* Poor: Marked change in the appearance of the treated breast involving more than a quarter of the breast tissue.

National Cancer Institute (NCI)

NRG Oncology

Radiation Therapy Oncology Group

All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.

Standard fractionation whole breast irradiation (WBI) with sequential boost.

Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery.

Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.

Whole Breast Irradiation + Sequential Boost

Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost

Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery.

Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.

Hypofractionated Whole Breast Irradiation + Concurrent Boost

Total

Age, Continuous

< 50 years

≥ 50 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

0 - Asymptomatic; 1 - Symptomatic but completely ambulatory; 2 - Symptomatic, \<50% in bed during the day; 3 - Symptomatic, \>50% in bed, but not bedbound; 4 - Bedbound; 5 - Death

Zubrod Performance Status

Resection Margin Status

Axillary Staging Method

Radiation Therapy Technique (plan at randomization)

Received Chemotherapy

Estrogen receptor (ER) Status

A histologic measure of how closely a cancer cell nucleus resembles that of a normal cell, or a measure of how abnormal a cancer nuclear is. It is generally graded as 1 (resembles normal), 2 (moderately abnormal), and 3 (markedly abnormal).

Histologic Grade

Overall cancer stage per American Joint Committee on Cancer (AJCC) 7th ed. combines tumor (T), regional lymph node (N), and distant metastasis (M) staging to determine an overall stage of 0, I, II, III, or IV, ranging from least to most advanced, respectively. The higher the number after the T, the larger the tumor or the more it has grown into nearby tissues. The higher the number after the N, the greater the involvement of regional lymph nodes. M0 indicates no distant metastasis.

Pathologic Stage

An oncotype recurrence score comes from an analysis of a sample of a cancer tumor to see the activity of certain genes that can affect the cancer's outcome and how likely it is to grow and spread. A score \>25 means you have a higher risk that the disease might come back. Both hormone treatment and chemotherapy are likely to be recommended.

Oncotype recurrence score > 25

Pathologic stage 0 breast cancer wtih nuclear grade 3 DCIS and patient age <50 years

Due to a lower than anticipated incidence of in-breast recurrence (IBR), the protocol was amended to allow for timely reporting of the trial results with at least 46 IBR events, while maintaining statistical integrity and reflecting current knowledge of the observed IBR incidence in the control arm.

Wendy Seiferheld

Assuming Arm 1 5-year IBR of 1.59%, for hypothesized upper bound hazard ratio (HR) of 2.12 (Arm 2 5-year IBR of 3.33%), 46 IBR events provide \>80% power to conclude non-inferiority with one-sided significance level = 0.05. Null hypothesis: HR ≥ 2.12 (inferior). Alternative hypothesis: HR \< 2.12 (non-inferior). See "Limitations and Caveats" section.

Whole Breast Irradiation + Sequential Boost (Arm 1)

Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2)

Percentage of Participants With In-breast Recurrence (Local Failure)

Percentage of Participants Alive

Percentage of Participants Alive Without Disease

Percentage of Participants Alive Without Distant Disease

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment

Quality of life population, with data at baseline and 3 years.

Change in Breast Cancer Treatment Outcome Scale (BCTOS) Cosmesis Subscale Score From Baseline to 3 Years

Quality of life population, with data at 3 years.

Percentage of Participants With a Physician-reported Cosmetic Score of Excellent or Good at 3 Years

Correlation Between Dose-volume Data and Both Adverse Events and Efficacy

The protocol did not provide sufficient detail to meet current National Cancer Institute requirements for release of specimens from the NRG Oncology tissue bank for the protocol-specified analysis, therefore no assays were performed, and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.

Translational Research of Single Nucleotide Polymorphisms (SNPs) in Transforming Growth Factor Beta 1 (TGFB1) and Ataxia-Telangiesctasia Mutated (ATM) Genes

Treatment Cost

Overall Study

Hypofractionated whole breast irradiation for early breast cancer with prescription dose 40Gy in 15 fractions in 3 weeks. Tumor bed is simultaneously integrated boosted to 48Gy.

deliver 40Gy/15Fx to whole breast with 48Gy/15fx simultaneously integrated to tumor bed

hypofractionated whole breast irradiation with simultaneously integrated boost

Xiaoli Yu, MD

Xiaoli Yu, MD,PhD

Jurui Luo, MD

The study was designed to evaluate the feasibility and safety of hypofractionated whole-breast irradiation with simultaneously integrated boost for early-stage breast cancer after breast conserving surgery in Chinese population.

Hypofractionated Whole-breast Irradiation With Simultaneously Integrated Boost For Early-Stage Breast Cancer After Breast-conserving Surgery

acute toxicity related to irradiation such as lung and skin

Fudan University

Associate Professor of department of radiation oncology

Symptoms and General Pathology

Recurrence

Neoplasm Recurrence, Local

Disease Attributes

Neoplastic Processes

HIOB: IOERT of 11.1 Gy followed by WBRT with 15 times 2.7 Gy per fraction.

IOERT single shot as a boost followed by hypofractionated WBRT (HIOB)

* IOERT is performed on mobile or fixed linacs
* Reference dose: 11 Gy specified as maximum dose, with a minimum target volume dose of 90% encompassing the PTV (i.e. 10 Gy).

WBRT

* must start within day 36- 56 postoperatively (week 6 - 8 p.o.) in case of adjuvant hormonal treatment (or no further tumor specific medication)
* In case of adjuvant chemotherapy, a time - gap between IOERT and WBRT up to 9 months is allowed.
* Single reference dose per fraction: 2,7 Gy (ICRU)
* Number of fractions: 15, Number of fractions per week: 5
* Total WBRT dose: 40,5 Gy

HIOB

Gerd Fastner, Assoc.Prof.

Title:

HIOB - Hypofractionated Whole-Breast Irradiation preceded by Intraoperative Radiotherapy with Electrons as anticipated Boost ISIORT- 01

HIOB is defined as hypofractionated WBRT (40,5 Gy in 2,7 Gy per fraction) preceded by an Intraoperative Boost to the tumor bed ( 90 % reference dose of 10 Gy, 11,1 Gy Dmax IOERT).

Primary endpoint is the proof of superiority of a new treatment regimen.

The HIOB study concept is supposed to test the hypothesis whether such a combined schedule is superior (or iso-effective) towards "standard" RT in terms of local control and cosmetic outcome.

In the vast majority of all publications, annual and 5 year in-breast recurrence rates following BCT showed a clear dependency on patient age within the following boundaries (primary references):

Age \> 50: Bartelink (standard): 0,7% (annual) 3,5% (5y) START B (best): 0,4 %(annual) 2,0% (5y)

Age 41-50: Bartelink (standard) 1,2% (annual) 6,0% (5y) Whelan (best) 0,72%(annual) 3,6% (5y)

Age ≥ 35-40 Bartelink (standard) 2% (annual) 10% (5y) Whelan (best) 0,72% (annual) 3,6% (5y)

long these three different age groups, benchmarking will be performed against the best published results following 'Golden Standard'RT, usually defined as conventionally fractionated WBRT with 50 Gy (25 x2) plus external tumor bed boost with 10-16 Gy electrons (5-8x2Gy).

Superiority is defined as going below the lower limit of the estimated 5 year local recurrence rate within the respective age group Inferiority is defined as crossing the respective upper limit .

Secondary endpoint:

Disease free survival

Tertiary endpoint: toxicity assessment (acute and late) including long term cosmetic evaluation

Study design and statistics:

* Prospective multicenter single-armed
* Sequential probability ratio test (SPRT)
* Separate analysis within three different age groups

Estimated Accrual time: strongly dependent on recruitment per year within the respective age group . Due to the statistical estimation of Szenario A and B the study will close after max. Time-period of 10 years in case of A or 6,4 years in case of B..

Principal investigators and study coordinators:

UC of Radiotherapy and Radio-Oncology UC of Special Gynecology and Breast Cancer Center Landeskrankenhaus Salzburg, Paracelsus University Clinics

Study population:

See Points 4.1 und 4.2 Inclusion/Exclusion criteria of the entire protocol

Operation:

* Lumpectomy / segmentectomy / tumorectomy with sufficient safety margins (see above). Lymph node assessment must follow a sentinel node concept.
* Perioperative antibiotic prophylaxis is mandatory
* After IORT, radio-opaque clips have to be fixed at the tumor bed.

Histology: R0-Resection is mandatory

Chemotherapy:

neoadjuvant:allowed adjuvant: allowed.

There are no limitations towards special chemotherapeutic schemes and schedules.

Radiotherapy:

IOERT

* IOERT is performed on mobile or fixed linacs
* Reference dose: 11 Gy specified as maximum dose, with a minimum target volume dose of 90% encompassing the PTV (i.e. 10 Gy).

WBRT

* must start within day 36- 56 postoperatively (week 6 - 8 p.o.) in case of adjuvant hormonal treatment (or no further tumor specific medication)
* In case of adjuvant chemotherapy, a time - gap between IOERT and WBRT up to 9 months is allowed.
* Single reference dose per fraction: 2,7 Gy (ICRU)
* Number of fractions: 15, Number of fractions per week: 5
* Total WBRT dose: 40,5 Gy

RT of regional lymphatics: exclusion criterion

Diagnostics of Local recurrence:

* yearly mammographies,
* optional breast sonography, MRI
* LR has to be histologically confirmed

Follow-up screening for detection of metastases (minimum requirements):

* Chest X-Ray, optional
* abdominal sonography, optional
* lab tests incl. tumor markers, optional

Assessment of acute toxicity of WBRT according to CTC-toxicity Scoring-systems:

Assessment of late toxicity according to LENT-SOMA scoring-systems

Assessment of cosmetic outcome according to 5-point- Scoring System (vanLimbergen) starting before WBRT, including photo documentation in standardized positions

Intra-Operative Electron Boost and Hypofractionated Whole-Breast Irradiation During Breast-conserving Treatment (BCT)

Hypofractionated Whole-Breast Irradiation Preceded by Intra-Operative Radiotherapy With Electrons as Anticipated Boost HIOB A New Option in Breast-Conserving Treatment for Operated Breast Cancer Stages I and II

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery	NCT01349322	Breast Cancer	Standard fracti... Hypofractionate... Concurrent boos... Sequential boos...	18 Years -	Radiation Therapy Oncology Group
Hypofractionated Whole-breast Irradiation With Simultaneously Integrated Boost For Early-Stage Breast Cancer After Breast-conserving Surgery	NCT02617043	Breast Cancer	hypofractionate...	18 Years - 60 Years	Fudan University
Hypofractionated Whole-breast Irradiation With Simultaneously Integrated Boost For Early-Stage Breast Cancer After Breast-conserving Surgery	NCT02617043	Breast Cancer	hypofractionate...	18 Years - 60 Years	Fudan University
Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery	NCT01349322	Breast Cancer	Standard fracti... Hypofractionate... Concurrent boos... Sequential boos...	18 Years -	Radiation Therapy Oncology Group
Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery	NCT01349322	Breast Cancer	Standard fracti... Hypofractionate... Concurrent boos... Sequential boos...	18 Years -	Radiation Therapy Oncology Group
Intra-Operative Electron Boost and Hypofractionated Whole-Breast Irradiation During Breast-conserving Treatment (BCT)	NCT01343459	Local Neoplasm ... Toxicity	HIOB	35 Years -	Paracelsus Medical University

Spots Global Cancer Trial Database for hypofractionated whole breast irradiation