Intercostobrachial Nerve Sparing to Reduce Post-Surgical Pain

Breast Cancer Clinical Trial

— INSPIRE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03421522
• Other study ID #: INSPIRE-001
• Status: Recruiting
• Phase: N/A
• Start date: October 15, 2019
• Est. completion date: December 1, 2020

Study information

• Verified date: December 2019
• Source: McMaster University
• Contact: Toni Tidy
• Phone: 905-525-9140
• Email: tonitidy[@]mcmaster.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 1, 2020
• Est. primary completion date: December 1, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Pilot Study

Inclusion Criteria:

1. Females aged 18 years and older.

2. Known or suspected invasive breast cancer.

3. Planned ALND (not sentinel lymph node biopsy) either alone or with planned mastectomy or breast conserving surgery.

4. The ICBN is preservable (as confirmed in the OR)

5. Cognitive ability and language skills required to complete the outcome measures.

6. Provision of informed consent.

Exclusion Criteria:

1. The patient has chronic pain or a chronic pain syndrome for which they have received daily medication (i.e. opioid, anti-convulsant, anti-spasmodic, anti-depressant, anti-inflammatory) or routine pain intervention (i.e. nerve blocks) during the past 3 months.

Note: Chronic pain refers to known chronic pain disorder (i.e. post-herpetic neuralgia, complex regional pain syndrome, fibromyalgia, diabetic neuropathy, post-stroke pain, etc.). The diagnosis for a 'chronic pain syndrome' is outlined by the use of pain medications and interventions. The pain medication must be used by the patient to treat pain. For a pain intervention to be considered routine, it must be given in its prescribed frequency during the past three months (e.g. a patient that has been prescribed to receive a nerve block once a month, received three nerve blocks in the past three months).

2. The patient has a prior history of completing ALND on the ipsilateral side.

3. Detectable metastatic disease at the time of initial diagnosis.

4. Planned bilateral ALND.

5. History of shoulder trauma or pathology on the same side as their breast cancer.

6. Preservation of the ICBN is not possible, in the judgement of the attending surgeon (as confirmed in the OR).

7. Anticipated problems with the patient being available for follow-up.

8. Incarceration.

9. The patient is or may be enrolled in a competing trial.

10. Other reason to exclude the patient, as specified.

Biomarker Sub-Study Eligibility:

All eligible patients who consent to participate in the INSPIRE trial will be asked to participate in the biomarker sub-study. Participants who decline to participate in the biomarker sub-study will still be enrolled into the INSPIRE trial. During the pilot phase of the INSPIRE trial, we will confirm our ability to obtain and analyze blood samples from = 90% of INSPIRE participants.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Chronic Pain
• Intercostal Pain
• Pain, Chronic
• Post-surgical Pain

Intervention

Other:
• ICBN preservation 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.

Locations

Country	Name	City	State
Canada	Juravinski Hospital	Hamilton	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
McMaster University	Hamilton Health Sciences Corporation

Country where clinical trial is conducted

Canada, 

References & Publications (24)

Abdullah TI, Iddon J, Barr L, Baildam AD, Bundred NJ. Prospective randomized controlled trial of preservation of the intercostobrachial nerve during axillary node clearance for breast cancer. Br J Surg. 1998 Oct;85(10):1443-5. — View Citation

Andersen KG, Kehlet H. Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention. J Pain. 2011 Jul;12(7):725-46. doi: 10.1016/j.jpain.2010.12.005. Epub 2011 Mar 24. Review. — View Citation

Angst F, Aeschlimann A, Stucki G. Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities. Arthritis Rheum. 2001 Aug;45(4):384-91. — View Citation

Brodke DJ, Saltzman CL, Brodke DS. PROMIS for Orthopaedic Outcomes Measurement. J Am Acad Orthop Surg. 2016 Nov;24(11):744-749. — View Citation

Busse JW, Bhandari M, Guyatt GH, Heels-Ansdell D, Kulkarni AV, Mandel S, Sanders D, Schemitsch E, Swiontkowski M, Tornetta P 3rd, Wai E, Walter SD; SPRINT Investigators & the Medically Unexplained Syndromes Study Group. Development and validation of an instrument to predict functional recovery in tibial fracture patients: the Somatic Pre-Occupation and Coping (SPOC) questionnaire. J Orthop Trauma. 2012 Jun;26(6):370-8. doi: 10.1097/BOT.0b013e31822421e2. — View Citation

Busse JW, Bhandari M, Guyatt GH, Heels-Ansdell D, Mandel S, Sanders D, Schemitsch E, Swiontkowski M, Tornetta P 3rd, Wai E, Walter SD; SPRINT Investigators. Use of both Short Musculoskeletal Function Assessment questionnaire and Short Form-36 among tibial-fracture patients was redundant. J Clin Epidemiol. 2009 Nov;62(11):1210-7. doi: 10.1016/j.jclinepi.2009.01.014. Epub 2009 Apr 11. — View Citation

Fries JF, Bruce B, Cella D. The promise of PROMIS: using item response theory to improve assessment of patient-reported outcomes. Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S53-7. — View Citation

Gherghe M, Bordea C, Blidaru A. Sentinel lymph node biopsy (SLNB) vs. axillary lymph node dissection (ALND) in the current surgical treatment of early stage breast cancer. J Med Life. 2015 Apr-Jun;8(2):176-80. — View Citation

Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being: a World Health Organization Study in Primary Care. JAMA. 1998 Jul 8;280(2):147-51. Erratum in: JAMA 1998 Oct 7;280(13):1142. — View Citation

Jenkinson C, Stewart-Brown S, Petersen S, Paice C. Assessment of the SF-36 version 2 in the United Kingdom. J Epidemiol Community Health. 1999 Jan;53(1):46-50. — View Citation

Khan JS, Devereaux PJ, LeManach Y, Busse JW. Patient coping and expectations about recovery predict the development of chronic post-surgical pain after traumatic tibial fracture repair. Br J Anaesth. 2016 Sep;117(3):365-70. doi: 10.1093/bja/aew225. — View Citation

Madden K, Scott T, McKay P, Petrisor BA, Jeray KJ, Tanner SL, Bhandari M, Sprague S. Predicting and Preventing Loss to Follow-up of Adult Trauma Patients in Randomized Controlled Trials: An Example from the FLOW Trial. J Bone Joint Surg Am. 2017 Jul 5;99(13):1086-1092. doi: 10.2106/JBJS.16.00900. — View Citation

Mintken PE, Glynn P, Cleland JA. Psychometric properties of the shortened disabilities of the Arm, Shoulder, and Hand Questionnaire (QuickDASH) and Numeric Pain Rating Scale in patients with shoulder pain. J Shoulder Elbow Surg. 2009 Nov-Dec;18(6):920-6. doi: 10.1016/j.jse.2008.12.015. Epub 2009 Mar 17. — View Citation

Reininga IH, Brouwer S, Dijkstra A, Busse JW, Ebrahim S, Wendt KW, El Moumni M. Measuring illness beliefs in patients with lower extremity injuries: reliability and validity of the Dutch version of the Somatic Pre-Occupation and Coping questionnaire (SPOC-NL). Injury. 2015 Feb;46(2):308-14. doi: 10.1016/j.injury.2014.08.042. Epub 2014 Sep 16. — View Citation

Salmon RJ, Ansquer Y, Asselain B. Preservation versus section of intercostal-brachial nerve (IBN) in axillary dissection for breast cancer--a prospective randomized trial. Eur J Surg Oncol. 1998 Jun;24(3):158-61. — View Citation

Sprague S, Leece P, Bhandari M, Tornetta P 3rd, Schemitsch E, Swiontkowski MF; S.P.R.I.N.T. Investigators. Limiting loss to follow-up in a multicenter randomized trial in orthopedic surgery. Control Clin Trials. 2003 Dec;24(6):719-25. — View Citation

Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain. 2004 Mar;5(2):133-7. — View Citation

Torresan RZ, Cabello C, Conde DM, Brenelli HB. Impact of the preservation of the intercostobrachial nerve in axillary lymphadenectomy due to breast cancer. Breast J. 2003 Sep-Oct;9(5):389-92. — View Citation

Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JW, Wang SJ. A classification of chronic pain for ICD-11. Pain. 2015 Jun;156(6):1003-7. doi: 10.1097/j.pain.0000000000000160. — View Citation

Trudel JG, Rivard M, Dobkin PL, Leclerc JM, Robaey P. Psychometric properties of the Health Utilities Index Mark 2 system in paediatric oncology patients. Qual Life Res. 1998 Jul;7(5):421-32. — View Citation

Wang L, Guyatt GH, Kennedy SA, Romerosa B, Kwon HY, Kaushal A, Chang Y, Craigie S, de Almeida CPB, Couban RJ, Parascandalo SR, Izhar Z, Reid S, Khan JS, McGillion M, Busse JW. Predictors of persistent pain after breast cancer surgery: a systematic review and meta-analysis of observational studies. CMAJ. 2016 Oct 4;188(14):E352-E361. doi: 10.1503/cmaj.151276. Epub 2016 Jul 11. Review. — View Citation

Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996 Mar;34(3):220-33. — View Citation

Warrier S, Hwang S, Koh CE, Shepherd H, Mak C, Carmalt H, Solomon M. Preservation or division of the intercostobrachial nerve in axillary dissection for breast cancer: meta-analysis of randomised controlled trials. Breast. 2014 Aug;23(4):310-6. doi: 10.1016/j.breast.2014.01.014. Epub 2014 Feb 24. Review. — View Citation

Zhang Y, Alyass A, Vanniyasingam T, Sadeghirad B, Flórez ID, Pichika SC, Kennedy SA, Abdulkarimova U, Zhang Y, Iljon T, Morgano GP, Colunga Lozano LE, Aloweni FAB, Lopes LC, Yepes-Nuñez JJ, Fei Y, Wang L, Kahale LA, Meyre D, Akl EA, Thabane L, Guyatt GH. A systematic survey of the methods literature on the reporting quality and optimal methods of handling participants with missing outcome data for continuous outcomes in randomized controlled trials. J Clin Epidemiol. 2017 Aug;88:67-80. doi: 10.1016/j.jclinepi.2017.05.016. Epub 2017 Jun 1. Review. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Persistent post-surgical pain (PPSP)	Post-surgery as defined by the World Health Organization (WHO).; The WHO's definition requires 4 criteria for the diagnosis of PPSP: Pain that began after surgery or a tissue trauma is experienced; The pain is in an area of preceding surgery or tissue trauma,; The pain has persisted for at least three months after surgery, and; The pain is not better explained by an infection, malignancy, a pre-existing pain condition or any other alternative cause.	12 months
Primary	Moderate-to-severe PPSP	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.	12 months
Primary	Biomarker Sub-Study: Cytokine Levels and PPSP	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	3 weeks, 3 months
Primary	Biomarker Sub-Study: Cytokine Levels Pre and Post-Op	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.	3 weeks
Secondary	Operative Time	Operative time will be measured from the time of the first incision until the time of closure of the incision.	12 months
Secondary	General physical functioning	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)	12 months
Secondary	General Mental 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)	12 months
Secondary	Upper limb-specific physical 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).	12 months
Secondary	Return to Work	We will document when participants, who were employed before their surgery, return to work.	12 months
Secondary	Adverse Events	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.	12 months
Secondary	Pain Interference	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.	12 months
Secondary	Use of Prescription Opioids	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.	12 months
Secondary	Return to household activities	We will document when participants return to their normal household activities.	12 months
Secondary	Return to leisure activities	We will document when participants return to their normal leisure activities.	12 months
Secondary	Return to pre-surgical functioning	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).	12 months

External Links

•   Breast cancer facts and figures 2013-2014. Atlanta: American Cancer Society; 2013
•   Busse JW, Bhandari M, Einhorn TA, Schemitsch E, Heckman JD, Tornetta P, 3rd, et al. Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial. Bmj. 2016;355:i5351.
•   Canadian Cancer Statistics
•   Hamner J, Dewitt B. The Development of a Preference-based Scoring System for PROMIS (PROPr): A Technical Report v 1.1. [Internet] 2017;available from: http://janelhanmer.pitt.edu/documents/technicalreportv1.1.pdf (accessed August 29, 2017).
•   K. M. Intercostobrachial syndrome after nerve-sparing axillary lymph node dissection. Eur J Cancer. 2014;50:S127.
•   Visnjevac OM, B. Postmastectomy pain syndrome: an unrecognized annual billion dollar national financial burden. J Pain 2013;14