Investigation of the Pain Relieving Properties of Lipotransplantation After Treatment for Breast Cancer
Condition: Chronic Pain
MeSH terms: Chronic Pain
Study type: Interventional

Summary: 
      Background

      In Denmark, breast cancer is the most common fatal cancer in women with more than 4700 new
      cases annually. Unfortunately, up to 60% of women who are treated surgically for breast
      cancer, will experience chronic pain as a consequence of the treatment. This state of chronic
      neuropathic pain is termed "Post Breast Therapy Pain Syndrome" or PBTPS.

      The purpose of the study

      The purpose of this study is to investigate whether transplantation of fat cells
      (lipotransplantation) to the pain affected mastectomy area, could have an analgesic effect in
      women who have developed PBTPS. Secondary, we wish to investigate if lipotransplantation has
      a beneficial effect on the quality of the skin and the scar in the area where the
      transplanted fat cells are placed.

      Hypotheses

        -  Lipotransplantation to the area under the scar tissue and the area under the
           pain-afflicted area reduces the pain in women with PBTPS.

        -  The neuropathic pain in PBTPS is correlated to the number of free nerve endings crossing
           the border between the dermis and the epidermis

        -  Lipotransplantation have a beneficial effect on the scar tissue structure and improves
           the skin quality.

      Patients

      Women who have undergone treatment for breast cancer and subsequently developed PBTPS. A
      total of 32 patients with PBTPS will be included.

      Methods

      Patients will be randomly assigned to receive either lipotransplantation or no active
      treatment. At three follow-up visits, the perceived pain of the patient and the skin and scar
      quality will be scored. In addition, a 3-mm biopsy will be taken from the skin on both the
      missing and the healthy breast, and from the mastectomy scar.

      The scoring of the perceived pain and the quality of the skin and the scar, allows us to
      investigate if the lipotransplantation have an effect on pain, and skin/scar quality.
      Additionally, the skin and scar biopsies will be examined on a microscopic level, in order to
      investigate why lipotransplantation has these effects.

      Conclusion

      In summary, the results of this project could help to increase our understanding of why some
      patients develop chronic neuropathic pain after mastectomy and radiotherapy. It is our hope
      that our results may contribute to the development of better and more effective treatment
      that will be beneficial for the project participants and future patients.
    

Detailed description: 
      Background

      In Denmark, breast cancer is the most common fatal cancer in women with more than 4700 new
      cases annually. All patients are treated according to national guidelines developed by the
      Danish Breast Cancer Cooperative Group (DBCG). Treatment primarily consists of surgical
      removal of all or parts of the breast and simultaneous removal of one-or lymph nodes in the
      ipsilateral axilla. Subsequently, there may be a need for additional treatment with
      chemotherapy, radiation and / or anti-hormonal therapy, in order to reduce the risk of
      recurrence.

      Up to 60% of women who are treated surgically for breast cancer, will experience chronic pain
      as a consequence of the treatment. This condition was previously referred to as "Post
      Mastectomy Pain Syndrome", but because the condition is also seen after less extensive forms
      of breast cancer surgery, the condition is now termed "Post Therapy Breast Pain Syndrome"
      (PBTPS). PBTPS is defined as a neuropathic pain condition with pain localized to the axilla,
      the medial part of the upper arm, chest and or chest wall of the side of surgery, lasting
      more than three months after surgery and / or the end of treatment.

      In 2011 Caviggioli et al. published a study where lipotransplantation to the mastectomy area
      was found to have a significant analgesic effect. The aforementioned study is to date the
      only published study in the field. However, it is not a randomized study. In order to obtain
      further evidence of the apparent beneficial effect of lipotransplantation on pain, the
      present study has been initiated.

      Lipotransplantation is a fast and relatively non-invasive technique which is described in
      detail by Coleman et al.. Additionally, in a study from 2008, Klinger et al. found that
      lipotransplantation to burn scars in the face resulted in a significant improvement in the
      patient's skin and scar quality and also reduced pain in the treated areas. The theoretical
      basis for the scar and skin modifying effects of lipotransplantation has not yet been finally
      understood. To the best of our knowledge, no studies have systematically investigated and
      analysed the effects of lipotransplantation on the irradiated mastectomy area on a
      histological level.

      The purpose of the study

      The purpose of this study is to investigate whether lipotransplantation to the pain affected
      mastectomy area, could have an analgesic effect in women affected by Post Breast Therapy Pain
      Syndrome. Secondary, we wish to investigate the scar and skin modulating effects of
      lipotransplantation to the same area.

      By carrying out immunohistochemical staining and subsequent stereoscopic microscopy of free
      nerve endings in the skin biopsies taken before and after lipotransplantationen we wish to
      determine whether changes in the number and type of free nerve endings is part of the
      mechanism of pain reduction.

      Hypotheses

        -  Lipotransplantation to the area under the scar tissue and the area under the
           pain-afflicted area reduces the pain in women with PBTPS.

        -  The neuropathic pain in PBTPS is correlated to the number of free nerve endings crossing
           the border between the dermis and the epidermis

        -  Lipotransplantation have a beneficial effect on the scar tissue structure and improves
           the skin quality.

      Patients

      Women who have undergone unilateral mastectomy for breast cancer at Aarhus University
      Hospital, Aarhus, Denmark and, if applicable, has finished their adjuvant postoperative
      radiation therapy at least 6 months ago. Patients must have had pain localized to the area of
      the missing breast for at least three months after adjuvant radiation therapy ended. A total
      of 32 patients with PBTPS will be included.

      Methods

      Patients with PBTPS are randomly assigned to receive either lipotransplantation or no active
      treatment.

      Regardless of randomization, the patient will be invited to three follow-up visits,
      respectively 3 and 6 months after inclusion/surgery. At each of the outpatient visits the
      participant will be asked to complete the DoloTest ® , VAS pain score and the Patient Scar
      Assessment Scale. The clinician will complete the Observer Scar Assessment Scale and record
      the consumption of pain medication. DoloTest ® is a validated, visual analogue questionnaire
      designed to assess the patients experienced pain and impact on the patients daily life. Three
      3-mm punch biopsies will be taken at inclusion, one from the mastectomy scar, one from the
      skin 2 cm above the mastectomy scar in the medioclavicular line, and one from the healthy
      skin on the health breast in an area corresponding to the other skin biopsy.

      The skin punch biopsies from the pain afflicted area will be fixed in 4% phosphate buffered
      paraformaldehyde. After freezing, the tissue samples are cut into 50-micron thick sections.
      Systematically sampled sections immunostained with rabbit anti-human Protein Gene Product 9.5
      (a neuron-specific protein), and DAB-marked goat anti-rabbit as the secondary antibody. The
      sections are then microscoped in an Olympus BX51 light microscope with an Olympus DP71
      digital camera and Prior motorized board connected to a computer with Newcast stereology
      software. Two goals can then be calculated: 1) the number of free nerve endings, which
      crosses the border between dermis and epidermis per mm 2) the average nerve fibre length
      density in the epidermis and / or dermis.

      The skin punch biopsies from the mastectomy scar are fixed in formaldehyde for embedding in
      paraffin. The tissue samples are cut into 1-2 micron thick sections and stained with
      Picrosirius red (PR) colour. By using polarized light microscopy, the various subtypes of
      collagen fibres may be visualized and differentiated. The thicker collagen fibres (type I)
      are red-orange-yellow and the thinner collagen fibres (type III) are green. Furthermore, the
      sections will be stained for elastin. Quantitatively, by means of the above-mentioned method,
      changes in the volume fraction of collagen type I and III, and elastin may be measured.

      Statistical analyzes

      The minimal clinically relevant difference the study is looking for, is a Visual Analog Pain
      score difference of 3. The common standard deviation was estimated from a similar study by
      Caviggioli et al. in 2011, and set to be 2.96 on the Visual Analog Pain scale. We assume that
      our standard deviation (SD) will be the same. Using the following formula: N = (Za + Zb)2 x
      SD2 / dif2 where Za and Zb are the standardized normal deviations corresponding to the
      selected levels of significance, SD is Standard Deviation and dif is the minimal clinically
      relevant difference the study is looking for. The result is 16 patients in each arm,
      totalling 32 patients, when the significance level is set at 5% and the power of the study is
      set to 80%. Statistical analyzes will be performed in collaboration with a biostatistician
      from the Health Sciences Institution, Aarhus University, Denmark.

      Economic Conditions

      The project is supported by: Faculty of Health Sciences, University of Aarhus with three full
      time equivalents, which is used to pay for full-time academic staff. Other project expenses
      are to be covered by independent foundations and endowments that do not have an influence on
      the study. None of the personnel in the project have a financial interest in the project.

      Compensation to the participating patients

      The participating patients in the study will not receive any financial compensation. However,
      documented travel expenses will be reimbursed.

      Recruitment of participants

      Patients are primarily recruited from a previous study, were a questionnaire was sent to all
      women having received an unilateral mastectomy at Aarhus University Hospital, in the period
      from 2009 to 2013. In the questionnaire, patients were asked to evaluate their pain in the
      different areas pertaining to PBTPS, and if they would allow our department to contact them
      in regards to the present study. If patients fulfilled the inclusion criteria, they are
      contacted by the primary investigator by telephone, and a meeting were the details of the
      study are presented is arranged. Patients with PBTPS could also be recruited during their
      routine visits at the department of oncology.

      The patients will always be offered at least 24 hours of consideration before deciding to
      give written consent to participate in the study. With the signing of the consent form, the
      patient accepts the terms and conditions in the study. The patient may at any time and
      without justification withdraw her consent to participate, without her decision affecting her
      present or future treatment or any other rights the patient may have.

      Publication of results

      Negative, inconclusive and positive results from the study will be published in
      internationally recognized, peer-reviewed, English-language journals with an interest in the
      field.

      Ethical statement, side effects and risks

      In the present project, data will be treated confidentially in accordance with the Danish Act
      on Processing of Personal Data. Participants shall be informed both in writing and orally
      prior to deciding to participate in the study. The participants are thus fully aware of the
      projects purpose, background and methods, as well as what is expected from the patient's role
      as a participant.

      The participating patients are in the lipotransplantation group, offered an active treatment,
      which if the current study program can confirm the foreign study, hopefully reduces their
      daily pain and discomfort and thereby also their consumption of analgesia. If the project
      provides positive results, the control group will, after the study has ended, be offered the
      same active treatment.

      The patients, which only after informed consent, is part of the project will, in connection
      with:

        1. Lipotransplantation in general anaesthesia; only be exposed to the risk associated with
           general anaesthesia. The patients in the present study have in relation to their
           previous surgery for breast cancer been exposed to one or more interventions in general
           anaesthesia.

        2. Risks related to the actual lipotransplantation. At the donor site, there is a risk for
           short-term tenderness and temporary discolouration. In the long term, a slightly rough
           surface of the skin may arise. The advantage of the harvest of the fat graft is that the
           patient achieves a visible improvement of the contour at the donor site.

        3. The risk related to the skin punch biopsies: apart from a small scar 1-3 mm
           corresponding to the place where the biopsy is collected, there is not assessed to any
           risk of permanent injury or damage.

      All interventions are carried out by experienced specialists in plastic surgery with several
      years experience with lipotransplantation. The general anaesthesia is performed by
      specialists in anaesthesiology, which are all part of the permanent team at the plastic
      surgery department and therefore familiar with providing anaesthesia during the described
      procedures.
    

Intervention name(s): Lipotransplantation
Intervention type(s): Other
Intervention description(s): Lipotransplantation in general anaesthesia to the mastectomy site
Other intervention name(s): Fat grafting; Fat transplantation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Post Breast Therapy Pain Syndrome; Lipotransplantation; Breast Cancer; Pain