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For participants randomized to the ICBN preserving technique, surgeons will perform axillary dissection in which the second ICBN, just inferior to the axillary vein, will be preserved.

For participants allocated to the usual surgical care arm, attending surgeons will perform a standard Level 1 and 2 axillary node dissection (sacrifice of the ICBN), either alone or with mastectomy or breast conserving surgery.

For participants randomized to the ICBN preserving technique, surgeons will perform axillary dissection in which the second ICBN, just inferior to the axillary vein, will be preserved. Surgeons will be asked to indicate whether the ICBN nerve was fully preserved, partially preserved, or sacrificed.

All study participants will receive anesthetic management at the discretion of the attending physician, which will be documented.

ICBN preservation surgery

Toni Tidy

Gina Del Fabbro

Susan Reid, MD

Susan Dr Reid

Jason Busse

Sheila Sprague

Sacrifice of the intercostobrachial nerve (ICBN) during surgery is associated with development of persistent post-surgical pain (PPSP), which affects up to 60% of breast cancer surgery patients. A large, definitive trial is needed to establish whether nerve preservation techniques are effective in reducing post-surgical pain after breast cancer surgery. If the effect of ICBN preservation is consistent with observational studies, the absolute reduction of rates of persistent pain would be considerable.The primary objective is to determine the effect of ICBN preservation, versus usual care, on the prevalence and intensity of PPSP at one year after breast cancer surgery involving axillary lymph node dissection (ALND). Within the larger INSPIRE pilot, we will also be conducting a biomarker sub-study. The objectives of the biomarker sub-study are: 1) to determine the association between pro-inflammatory cytokine levels and the presence and intensity of persistent pain at 3 weeks, and 3 months post-surgery, and) 2) to determine the effect of study intervention on the change in cytokine levels (pre-operative to post-operative) in participants who consent to participate in the sub-study.

A 2016 systematic review that included 30 observational studies (n= 19,813 patients) found high quality evidence that axillary lymph node dissection (ALND) is associated with a 21% absolute risk increase of PPSP (95% CI = 13% to 29%). In many cases of breast cancer, surgery involves axillary approaches; however, preliminary evidence suggests that preservation of the intercostobrachial nerves (ICBN) may reduce the incidence of PPSP after axillary clearance. A 2014 systematic review found 3 small, single-center randomized controlled trials (RCTs), that enrolled a total of 309 patients, and explored the effect of ICBN preservation versus sacrifice during breast cancer surgery. This review found that division of the ICBN was associated with higher risk of sensory deficits, and that nerve preservation techniques increased the median operating time by 5 minutes. Due to limitations of existing evidence, clinical practice guidelines currently provide no recommendations on whether the ICBN should be preserved during axillary lymph node dissection.A large, definitive trial is needed to establish whether nerve preservation techniques are effective in reducing PPSP after breast cancer surgery involving ALND. If all the apparent effect of axillary dissection is associated with lack of ICBN preservation, the absolute reduction of rates of PPSP would be considerable. Furthermore, nerve sparing requires no specialized equipment, suggesting that scalability will be highly feasible.

In addition, there is substantial evidence that neuro-inflammation as a result of neural damage leads to peripheral and central changes that can be described as peripheral and central sensitization, leading to PPSP. As such, we will be conducting a biomarker sub-study as part of the pilot program. Identification of biomarkers to correlate with the development of neuropathic pain may facilitate identification of individuals at risk for development of PPSP at an early stage. The INSPIRE trial provides an important opportunity to compare patients before and after nerve injury to further explore the association of persistent pain with cytokine biomarkers. The findings will improve our mechanistic understanding of PPSP.

For participants randomized to the ICBN preserving technique, surgeons will perform axillary dissection in which the second ICBN, just inferior to the axillary vein, will be preserved

Eligible participants will be randomized to one of two treatment groups: 1) ICBN preservation, or 2) usual surgical technique (ICBN sacrifice). Due to the nature of the intervention, it will not be feasible to blind the treating surgeons or the study personnel. The patients, data analysts, and those interpreting the study results will be blinded to treatment allocation.To ensure concealed allocation, eligible patients will be randomized using the randomization function within the REDCap Cloud electronic data capture system. Treatment allocation will be stratified by clinical site to account for systematic differences in surgeons and peri-operative care. To avoid crossover between treatment allocation, randomization will take place in the operating room after the surgeon has confirmed that the participant is a candidate for ICBN preservation.

Intercostobrachial Nerve Sparing to Reduce Post-Surgical Pain

Intercostobrachial Nerve Sparing in Breast Cancer Surgery to Reduce Persistent Post-surgical Pain - an International Randomized Controlled Trial

Post-surgery as defined by the World Health Organization (WHO).

The WHO's definition requires 4 criteria for the diagnosis of PPSP:

1. Pain that began after surgery or a tissue trauma is experienced;
2. The pain is in an area of preceding surgery or tissue trauma,
3. The pain has persisted for at least three months after surgery, and
4. The pain is not better explained by an infection, malignancy, a pre-existing pain condition or any other alternative cause.

We will establish the severity of PPSP with an item from the Brief Pain Inventory Short Form (BPI-SF), which asks patients to report their 'average' pain intensity rating in the past 24 hrs, on a scale of 0 (no pain) to 10 (maximum pain).

As per the BPI-SF scoring system, we will define moderate-to-severe pain as scores of ≥4 out of 10.

We will determine the correlation between pro-inflammatory cytokine levels and the presence and intensity of persistent pain at 3 weeks, and 3 months post-surgery

We will determine the effect of the study intervention on the change in cytokine levels (pre-operative to post-operative) in participants who consent to participate in the sub-study.

Operative time will be measured from the time of the first incision until the time of closure of the incision.

Short Form-36 Health Assessment Survey (SF-36) Physical Component Summary score.

The range of possible scores goes from 0 (worst possible physical functioning) to 100 (best possible physical functioning)

Short Form-36 Health Assessment Survey (SF-36) Mental Component Summary score.

The range of possible scores goes from 0 (worst possible mental functioning) to 100 (best possible mental functioning)

The Quick-Disability Arm Shoulder Hand Survey (Quick-DASH).

An 11-item scale that measures physical function in people with any or multiple musculoskeletal disorders of the upper limb.

The range of scores goes from 0 (worst possible functioning) to 100 (best possible functioning).

We will document when participants, who were employed before their surgery, return to work.

All adverse events will be documented on the study specific case report forms. An independent medical monitor will also review each adverse event to determine its relatedness to the surgical treatment.

Item PAININ18 of the PROMIS will be used to determine the proportion of patients who report somewhat-to-very much pain interference over 12 months post-surgery.

This item is scored from 0 (not at all) to 4 (very much), and we will use a cut-off value of 2 (somewhat) or higher to define an event.

We will capture the proportion of patients who are prescribed an opioid at 3, 6, 9 and 12-months post-surgery, including the type and dose.

We will document when participants return to their normal household activities.

We will document when participants return to their normal leisure activities.

We will document when participants achieve 80% of their pre-surgery function, as measured on a percentage scale of 0% (no function) to 100% (full pre-surgical function).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Intercostobrachial Nerve Sparing to Reduce Post-Surgical Pain	NCT03421522	Post-surgical P... Pain, Chronic Intercostal Pai... Breast Cancer	ICBN preservati...	18 Years -	McMaster University
Intercostobrachial Nerve Sparing to Reduce Post-Surgical Pain	NCT03421522	Post-surgical P... Pain, Chronic Intercostal Pai... Breast Cancer	ICBN preservati...	18 Years -	McMaster University

Spots Global Cancer Trial Database for intercostal pain