Trial document




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  DRKS00014558

Trial Description

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Title

Preoperative fractionated Stereotactic Radiosurgery for Breast Cancer (PROBE)

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Trial Acronym

PROBE

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URL of the Trial

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Brief Summary in Lay Language

The purpose of this study is to investigate whether a new type of radiotherapy can be used to achieve a targeted, gentle and adequate treatment for cancer by treating the non-infallen breast. The radiation dose is applied in such a way that only the immediate environment of the tumor is treated, the tumor is "paralyzed" so to speak, and then surgically removed completely. In contrast to this, it is common practice to treat the entire breast after surgery.
In the current standard treatment, the tumor is removed first, and the entire breast as well as the tumor bed irradiated, with a duration of 5 to 7 weeks. We investigate whether the same effect can be achieved with a only one-week therapy, but which, thanks to the visibility of the disease, is performed before the surgery.
The newly investigated type of radiotherapy uses modern therapies, which allow the optimum geometry to be taken into account from many angles, thus pretreating non-insensitive tissues. Overall, the radiation exposure of the entire body is lower.

We hope that this new method of treatment will be a significantly shorter, more pleasant and safe form of radio therapy for the patient, as well as being cosmetically and oncologically not inferior to today's therapies.
Within the scope of the study, the cosmetic results with measurement and photographic documentation of the breast are elaborated, so that a possibly gentle effect of the small preoperative radio therapy can be objectively mediated. Anonymised excerpts with the breast and the breasts before and after surgery can appear at congresses and further trainings as well as in publications. However, a conclusion on the identity will not be possible.

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Brief Summary in Scientific Language

Breast-conserving therapy consisting of lumpectomy and postoperative radiotherapy of the entire breast has been standard for several decades. Investigative approaches to improve on therapy by respecting risks such as size, grade, invasiveness or associated carcinoma in-situ guides research to tailored approaches, generally reducing treatment length, such as accelerated postoperative partial breast irradiation, postoperative partial breast interstitial therapy or intraoperative radiotherapy. Treatment with surgery alone remains reserved to the elderly with small tumor without any signs of risk and suitable for adjuvant systemic therapy.
Preoperative RT is an effective modality for complex multimodal treatment, and has been investigated by several groups in breast cancer. Advances in modern RT lead to delivering IR in a controlled and reproducible manner and partial breast therapy seems to be result in similar local tumor control rates as whole breast RT.
From experience with rectal carcinoma and sarcoma, we know that preoperative RT is associated with high rates of local tumor control. The mechanism is primarily through the effect of IR on the ability to reduce viability of cancer cells when displaced from the tumor bed to peritumoral areas by seeding during surgery. However, the cytotoxic effects of IR may lead to tumor cell kill resulting in definitive tumor control without the need of subsequent surgery such as carcinoma of the anal canal or head-and-neck.
The clinical benefit of modified sequencing of APBI before resection has not been conclusively investigated; especially the best dose to be used has not been defined. The effects of fractionated radiotherapy with single high doses have not been investigated in breast cancer.
We plan to irradiate the tumor and surrounding tissue with various dose levels escalating the dose from 25 to 45 Gy delivered on 5 consecutive working days. The BED of the investigated doses spans across the current conventionally fractionated dose intensity for the boost volume after lumpectomy of breast cancer, being 33 x 2 Gy with a BED of 110.

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Organizational Data

  •   DRKS00014558
  •   2018/06/28
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  •   yes
  •   Approved
  •   3/18, Ethik-Kommission des Landes Sachsen-Anhalt
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Secondary IDs

  •   2017-003878-13 
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Health Condition or Problem studied

  •   C50 -  Malignant neoplasm of breast
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Interventions/Observational Groups

  •   Test arm: therapy of the primary tumor with SBRT dose escalation.
    The respective doses are administered on 5 consecutive working days, according to the intervention period.

    Dose level 1: 5 x 5 Gy if no toxicity after 6 weeks: escalation
    Dose level 2: 5 x 6 Gy if no toxicity after 6 weeks: escalation
    Dose level 3: 5 x 7 Gy if no toxicity after 6 weeks: escalation
    Dose level 4: 5 x 8 Gy if no toxicity at 6 weeks: escalation
    Dose level 5: 5 x 9 Gy
    If 1/5 patients have a serious adverse reaction: The dose level is repeated with 5 other patients, so there are 10 patients at the dose level. If 1/10 patients have severe side effects: The next higher dose level will be initiated. IF ≥2 / 10 have severe side effects, the dose level is considered too toxic to be used in clinical routine. The previous dose level is then used to treat 25 patients. IF ≥2 / 10 patients experience severe toxicity in the first group, the study will be discontinued. If ≥3 patients are observed as a result of severe toxicity, the study will be discontinued.

    Operation is 6 weeks (+/- 1 week) after the last day of RT: R0

    A long-term efficacy trial as defined by the efficacy of a Phase II study is warranted when ≤2 local recurrences occurred in the 25 patients.
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Characteristics

  •   Interventional
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  •   Other
  •   Open (masking not used)
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  •   Other
  •   Other
  •   Other
  •   I-II
  •   N/A
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Primary Outcome

Acute toxicity, dose finding
Follow up investigations 1-3 years after surgical intervention every 6 months
Follow up investigations 4-5 years after surgical intervention every 12 months
Follow up investigations 5-15 years after surgical intervention every 24 months

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Secondary Outcome

- Regression score
- local tumor control rates at 5 years
- DFS
- OS
- late toxicity according to Common Terminology Criteria for Adverse Events of the National Cancer Institute, Version 4.0
- QOL using EORTC QLQ-C30
- Cosmetic changes after 1, 3, & 5 yrs (BCCT.core)
- immunological assessment at diagnosis:
Histology: ratio of tumor cells to non-tumorous tissue, ER, PR, Her-2/neu, Ki-67; PD-L1, CD8 pos. cells, CD4 pos. cells, CD11 pos. cells, CD25 pos. cells, CD56 pos. cells, IHC staining of factor VIII, TGF-beta, FGF, IFN-beta und IFN-gamma, TNF-alpha, cleaved caspase-3
- Immunological assessment of the surgical specimen:
ratio of tumor cells to non-tumorous tissue, ER, PR, Her-2/neu, Ki-67; PD-L1, CD8 pos. cells, CD4 pos. cells, CD11 pos. cells, CD25 pos. cells, CD56 pos. cells, IHC staining of CD34, TGF-beta, FGF, IFN-beta und IFN-gamma, TNF-alpha, cleaved caspase-3
Follow up investigations 1-3 years after surgical intervention every 6 months
Follow up investigations 4-5 years after surgical intervention every 12 months
Follow up investigations 5-15 years after surgical intervention every 24 months

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • other 
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Recruitment

  •   Planned
  •   2018/07/01
  •   50
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Female
  •   50   Years
  •   no maximum age
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Additional Inclusion Criteria

age ≥ 50 years

Invasive ductal, monofocal carcinoma of the breast G1– G3, cT1c to cT2 (1 cm to 4 cm) without any evidence of lobular carcinoma or in situ DCIS (>10%)

Complete histological characterization including: ER expression status, PR expression status, Her-2/neu expression status, Ki-67 und PD-L1

cN0

no indication for preoperative chemotherapy

The patient is candidate for primary breast-conserving resection and sentinel lymph node biopsy.

Ability to understand protocol and ability and willingness to comply with follow-up

The patient agrees, that her case will be discussed repeatedly in interdisciplinary tumor boards.

Negative pregnancy test in premenopausal patients

If premenopausal and sexually active, maintained contraception for at least 12 months after radiotherapy

The patient agrees to have an Au-tissue marker placed to define localization oft the tumor.

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Exclusion Criteria

previous radiotherapy of affected breast

Pregnancy test positive

rheumatoide arthritis, systemic lupus erythematoides, scleroderma

breast implant of affected breast

Lack of tissue marker at the start of radiotherapy

Planned mastectomy or skin-sparing mastectomy

Planning constrains cannot be achieved (Drop-out after planning)

Inability to tolerate prone positioniong during radiotherapy.

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Addresses

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    • Städtisches Klinikum Dessau
    • Auenweg 38
    • 06847  Dessau-Rosslau
    • Germany
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    • Städtisches Klinikum Dessau
    • Mr.  Dr.  Michael  Schlegel 
    • Auenweg 38
    • 06847  Dessau-Rosslau
    • Germany
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    • Städtisches Klinikum Dessau
    • Mr.  Prof. Dr.  Ilja  Ciernik 
    • Auenweg 38
    • 06847  Dessau-Rosslau
    • Germany
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    • Städtisches Klinikum Dessau
    • Mr.  Prof. Dr.  Ilja  Ciernik 
    • Auenweg 38
    • 06847  Dessau-Rosslau
    • Germany
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Sources of Monetary or Material Support

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    • Städtisches Klinikum Dessau
    • Auenweg 38
    • 06847  Dessau-Rosslau
    • Germany
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Status

  •   Recruiting withdrawn before recruiting started
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Trial Publications, Results and other Documents

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