Prophylactic LYMphatic Reconstruction (LYMbR) to Prevent Lymphedema After Node Dissection for Cutaneous Malignancies

Malignant Skin Neoplasm Clinical Trial

— LYMbR  

Official title:

Prophylactic LYMphatic Reconstruction (LYMbR) to Prevent Lymphedema

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05136079
• Other study ID #: PLVA-2021
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: January 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: November 2021
• Source: Alberta Health Services, Calgary
• Contact: Carmen Webb, MA
• Phone: 403-521-3012
• Email: carmen.webb[@]ahs.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background: Lymphedema following lymph node dissection is a chronic condition that can limit physical, occupational, and social participation, impact self-image, and result in financial burden. Studies have reported lymphedema incidence rates of 39% to 73% following node dissection.

Lymphaticovenous anastomosis (LVA) has been previously used to treat established lymphedema. More recently, with imaging capabilities guided by blue dye and indocyanine green dye, the possibility of prophylactic LVA has become feasible. A 2018 systematic review of 12 studies utilizing prophylactic LVA during lymphadenectomy indicated a 2/3 reduction in the risk of lymphedema. The literature yet lacks any phase III studies with stringent controls and long term follow-up.

Objectives: To assess (primary endpoint) the impact of prophylactic LVA on presence or absence of lymphedema post axillary or groin lymphadenectomy and participant quality of life. To assess (secondary endpoint) the incidence of complications related to nodal dissection.

Methods: This is a phase III RCT, block randomized for upper and lower extremities, recruiting adult patients planned for an axillary or groin node dissection as a result of cutaneous malignancy. Analysis of rates of lymphedema and quality of life reports will be done.

Significance: Lymphedema is a feared outcome of surgical cancer care. Its impact on patients' daily lives is profound. A reduction of incidence of this debilitating condition by 2/3 would have significant impact on numerous lives and could also reduce the health system resources needed for its management.

Description:

Trial Objective: To ascertain the efficacy and impact of prophylactic lymphaticovenous anastomosis for prevention of lymphedema in cutaneous malignancy patients undergoing axillary or groin node dissection as part of cancer treatment. To determine quality of life impact, if any, for patients who receive this treatment. To determine incidence of complications related to nodal dissection are reduced with LVA.

Cancer-related lymphedema (CRLE) is a complex and lifelong implication of cancer treatment. Centres have reported rates of lymphedema following axillary node dissection of 39% (53% following adjuvant radiotherapy), and exceeding 73% following groin node dissection. Lymphedema can have significant quality of life (QoL) implications. Treatment, though helpful, is often burdensome, can require a second party to accomplish, and can be financially draining. Further, lymphedema is a chronic condition that cannot be eliminated once established. Many everyday activities, including self-care, employment, and social participation, as well as self-image, can be negatively impacted.

Given the high prevalence of CRLE, there is an urgency to investigate prophylaxis where possible. Prophylactic lymphaticovenous anastomosis offers this opportunity.

Although lymphaticovenous anastomosis (LVA) has been used for decades to treat existing lymphedema, more recently prophylactic LVA has been explored. Jørgensen et al's 2018 systematic review of 12 studies utilizing prophylactic LVA in cancer patients undergoing axilla or groin lymphadenectomy indicated a 2/3 reduction of CRLE in those treated prophylactically compared to those who did not receive prophylactic treatment.

More recently, Cakmakoglu et al reported on an immediate prophylactic approach whereby the LVA is performed at the time of nodal dissection utilizing fluorescing indocynanine green (ICG) and an operating microscope. This approach aided identification and assessment of the viability of lymphatic vessels in 96% of study cases, thereby augmenting the surgeon's ability to identify and choose the most appropriate vessels. Cakmakoglu's team performed the technique successfully on 22 patients. Of this 22, a single patient developed CRLE during the follow-up period (3 patients died of disease during the follow-up period but showed no sign of CRLE at their demise).

The outlook for LVA in combination with ICG looks promising but, to date, there has not been a Randomized Control Trial (RCT) on this prophylactic LVA technique. Thus, there is a need for robust RCTs utilizing a control group, having clearly defined outcome measures, investing in a significant follow-up period, and integrating blinded assessment in order to objectively demonstrate the impact of prophylactic LVA for patients.

Jørgensen et al's 2018 systematic review of prophylactic LVA case series and studies noted that, while the results were remarkable, the studies collected for the review did not have adequate control for bias and were quite heterogeneous in their cancer type, lymphadenectomy location, lymphedema classification, and assessment measures. QoL measures were not regularly integrated into assessment. Follow-up times varied from 6 months to 69 months with only 3 studies following for a minimum of 24 months.

Trial description:

Study participants will be comprised of patients undergoing lymphadenectomy for cutaneous malignancy. The participants will be block (axilla, groin) randomized using 2 equal groups (control/intervention) of 20 participants each. Participants assigned to the intervention arm will undergo prophylactic LVA as an addendum to their lymph node dissection. This will take place at time of lymphadenectomy surgery. Control participants will not have prophylactic LVA. Both groups will be blinded to treatment.

All participants will have limb volume measurements and photographs taken and the LYMQOL lymphedema-specific quality of life questionnaire administered at baseline (date of surgery) and at 6 month intervals for 24 months. Their recovery and surgical complications will be monitored as per the surgeon's usual followup schedule. At 24 months each participant will undergo a radionuclide lymphoscintigraphy to assess function and health of their lymphatic system. Unblinding will taken place at this juncture except in cases where necessary to unblind earlier to provide exceptional care.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult persons (>18 years of age) undergoing axilla or groin lymphadenectomy as part of cutaneous malignancy management.

Exclusion Criteria:

• Patients receiving a sentinel lymph node biopsy alone

• Patients with untreated in-transit disease on the upper or lower extremities

• Patients with established preoperative lymphedema

• Patients with post-thrombotic syndrome

• Pregnant patients

• Patients with a previous history of radiation therapy to the affected nodal basin or extremity

Related Conditions & MeSH terms

• Lymphedema
• Lymphedema of Limb
• Malignant Skin Neoplasm
• Skin Neoplasms

Intervention

Procedure:
• Prophylactic lymphaticonvenous anastomosis
Prophylactic lymphaticovenous anastomosis is an immediate prophylactic approach whereby the lymphaticovenous anastomosis is performed at the time of nodal dissection utilizing fluorescing indocynanine green (ICG) and an operating microscope.

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta

Sponsors (3)

Lead Sponsor	Collaborator
Alberta Health Services, Calgary	Tom Baker Cancer Centre, University of Calgary

Country where clinical trial is conducted

Canada, 

References & Publications (14)

Baibergenova A, Drucker AM, Shear NH. Hospitalizations for cellulitis in Canada: a database study. J Cutan Med Surg. 2014 Jan-Feb;18(1):33-7. — View Citation

Brayton KM, Hirsch AT, O Brien PJ, Cheville A, Karaca-Mandic P, Rockson SG. Lymphedema prevalence and treatment benefits in cancer: impact of a therapeutic intervention on health outcomes and costs. PLoS One. 2014 Dec 3;9(12):e114597. doi: 10.1371/journal.pone.0114597. eCollection 2014. — View Citation

Cakmakoglu C, Kwiecien GJ, Schwarz GS, Gastman B. Lymphaticovenous Bypass for Immediate Lymphatic Reconstruction in Locoregional Advanced Melanoma Patients. J Reconstr Microsurg. 2020 May;36(4):247-252. doi: 10.1055/s-0039-3401829. Epub 2019 Dec 31. — View Citation

Campanholi LL, Duprat JP, Fregnani JHTG. Incidence of le due to treating cutaneous melanoma. J Lymphoedema. 2011; 16(1): 30-34.

Dunberger G, Lindquist H, Waldenström AC, Nyberg T, Steineck G, Åvall-Lundqvist E. Lower limb lymphedema in gynecological cancer survivors--effect on daily life functioning. Support Care Cancer. 2013 Nov;21(11):3063-70. doi: 10.1007/s00520-013-1879-3. Epub 2013 Jun 29. — View Citation

Garza RM, Chang DW. Lymphovenous bypass for the treatment of lymphedema. J Surg Oncol. 2018 Oct;118(5):743-749. doi: 10.1002/jso.25166. Epub 2018 Aug 11. Review. Erratum in: J Surg Oncol. 2019 Jun;119(7):1031. — View Citation

Gebruers N, Verbelen H, De Vrieze T, Coeck D, Tjalma W. Incidence and time path of lymphedema in sentinel node negative breast cancer patients: a systematic review. Arch Phys Med Rehabil. 2015 Jun;96(6):1131-9. doi: 10.1016/j.apmr.2015.01.014. Epub 2015 Jan 28. Review. — View Citation

Hanson SE, Chang EI, Schaverien MV, Chu C, Selber JC, Hanasono MM. Controversies in Surgical Management of Lymphedema. Plast Reconstr Surg Glob Open. 2020 Mar 27;8(3):e2671. doi: 10.1097/GOX.0000000000002671. eCollection 2020 Mar. — View Citation

Hormes JM, Bryan C, Lytle LA, Gross CR, Ahmed RL, Troxel AB, Schmitz KH. Impact of lymphedema and arm symptoms on quality of life in breast cancer survivors. Lymphology. 2010 Mar;43(1):1-13. — View Citation

Jørgensen MG, Toyserkani NM, Sørensen JA. The effect of prophylactic lymphovenous anastomosis and shunts for preventing cancer-related lymphedema: a systematic review and meta-analysis. Microsurgery. 2018 Jul;38(5):576-585. doi: 10.1002/micr.30180. Epub 2017 Mar 28. — View Citation

Loprinzi PD, Cardinal BJ, Winters-Stone K, Smit E, Loprinzi CL. Physical activity and the risk of breast cancer recurrence: a literature review. Oncol Nurs Forum. 2012 May 1;39(3):269-74. doi: 10.1188/12.ONF.269-274. Review. — View Citation

Paskett ED, Dean JA, Oliveri JM, Harrop JP. Cancer-related lymphedema risk factors, diagnosis, treatment, and impact: a review. J Clin Oncol. 2012 Oct 20;30(30):3726-33. doi: 10.1200/JCO.2012.41.8574. Epub 2012 Sep 24. Review. — View Citation

Rockson SG. Causes and consequences of lymphatic disease. Ann N Y Acad Sci. 2010 Oct;1207 Suppl 1:E2-6. doi: 10.1111/j.1749-6632.2010.05804.x. — View Citation

Tiwari P, Coriddi M, Salani R, Povoski SP. Breast and gynecologic cancer-related extremity lymphedema: a review of diagnostic modalities and management options. World J Surg Oncol. 2013 Sep 22;11:237. doi: 10.1186/1477-7819-11-237. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence or absence of lymphedema at 24 months post axillary or groin lymphadenectomy as assessed by limb volume over time.	Using a non-stretch measuring tape, circumferential measurements at 4cm intervals along the length of the contralateral limbs will be taken pre-surgery (baseline) and at 24 months. Limb volumes will be calculated. In the limb impacted by surgery, a 10% increase in volume from baseline to 24 months will be indicative of the development of lymphedema. In the case of significant weight gain or loss, comparison with the volume of the contralateral limb will also be used to evaluate presence of lymphedema in the surgical limb.	24 months
Primary	Quality of life impact as measured by LYMQOL PROM	A lymphedema quality of life patient reported outcome measure with specific arm and leg questionnaires called the LYMQOL will be used to measure quality of life. The scale uses a 4 point system for the majority of questions wherein a higher score indicates that lymphedema is having a greater negative impact on quality of life. A single final question uses a 10 point scale (poor to excellent) to rate one's quality of life overall with a higher score indicating greater quality of life. Comparison of quality of life scoring from baseline (pre-surgery) with scoring at 24 months post-surgery.	24 months
Secondary	Incidence of evidence of acute post-operative surgical complications	Diagnosis of complications such as cellulitis, dehiscence, lymphocele, and/or prolonged need for drain over 30days	24 months