The LYMPH Trial - Surgical versus Conservative Complex Physical Decongestion Therapy for Chronic Breast Cancer-Related Lymphedema: A Pragmatic, Randomized, Multicenter Superiority Trial

Chronic breast cancer related lymphedema (BCRL) is caused by lymphatic system
failure after sentinel lymph node biopsy (SLNB) or axillary lymph node
dissection (ALND) and/or radiotherapy. It is a debilitating condition resulting
in physical and psychological morbidity, i.e. an affected arm which may become
swollen, heavy and deformed, and it is, tense, painful and/or prone to
infections. Further, BCRL can also result in a significant financial burden to
patients and society.

To date, conservative complex physical decongestion therapy (CDT) is the gold
standard for BCRL and includes manual lymphatic drainage, local compression
with bandages and garments, physical exercises and meticulous skin care. It is,
however, too often ineffective to prevent stage progression in curing BCRL and
purely symptomatic.

Lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) are
two surgical techniques that, in contrast to CDT, are able to actually address
the underlying causes and eventually restore the lymphatic drainage. LVA
achieves this by creating numerous bypasses between lymphatic vessels and
venules allowing the drainage of excessive fluid within the subcutaneous
tissues into the venous system, while VLNT usually brings functioning lymph
nodes to an area devoid of lymph nodes or with dysfunctional lymph nodes, thus
enabling the spontaneous development of new lymphatic basin pathways. Both
techniques have shown very promising results with low complication rates and
improved Quality of Life (QoL) for the patients. However, no multicentric
randomized controlled trial (RCT) has yet prospectively evaluated the
superiority of these surgical techniques over CDT alone, limiting patient*s
access to most effective treatment available. Requests for cost reimbursement
must still be submitted to insurance companies in most countries and are often
rejected, thus delaying surgical treatment and resulting in prolonged suffering
of affected patients. This is untenable seeing as affected patients suffer from
a heavy physical, psychological and financial burden. This pragmatic,
randomized, multicenter trial aims to establish a solid scientific basis
assessing the superiority of surgical treatment over CDT alone.

Primary Objective:
The primary objective of this trial is to test whether lymphatic surgery
provides better QoL (assessed with the Lymph-ICF-UL, upper limb, questionnaire)
15 months after randomization (and therefore about one year after surgery)
compared to conservative treatment only for patients with chronic lymphedema
(LE).

Secondary Objectives:
Secondary objectives will compare lymphatic surgery versus conservative
treatment only in terms of further QoL aspects, arm volume, safety, burden on
patients and pain.

Pragmatic, randomized, international, multicenter superiority trial

Patients randomized to the control arm will receive the standard of care
treatment CDT. A treatment example/suggestion is described in detail in
protocol section 3.4.2, but according to the pragmatic study design, CDT will
not be standardized.

Patients randomized to the interventional arm should undergo surgical treatment
(LVA or VLNT with or without liposuction) as soon as possible but latest 3
months after randomization.

According to the pragmatic study design, the intervention will not be
standardized to assure that some flexibility is allowed that offers surgeons
considerable leeway how to perform lymphatic surgery, which resembles the
flexibility in usual care. However, the key aspects of the preoperative workup
will be documented and the intervention including the surgical technique,
number of LVAs, time of surgery, and practical details.
Patients randomized to the interventional arm will also receive CDT as SOC as
described in protocol chapter 3.4.1.

Due to the nature of the study, patients and surgical teams cannot be blinded
to allocation and surgical procedure.
Examples of the possible surgical interventions are described in detail in
protocol section 3.4.1.

Burden/risks:
- Very common side effects are, as with (almost) all operations, pain,
bleeding/bruising and swelling.
- Common side effects are, as with (almost) all operations, delayed wound
healing and wound infections.
- A rare side effect in patients with lymph node transplantation from the thigh
is lymphedema at the donor site. No other side-effects are currently known.
- Quality of life and pain questionnaires: You will probably need about 10
minutes to fill in the questionnaires. You can usually do this while waiting
for the appointment in the waiting room. If you do not want to or cannot answer
individual questions, this is fine.
- Measurement of arm circumference: For the uniform recording of (changes in)
arm circumference, the study team will carry out the appropriate measurement on
you. This should take about 5 minutes.
- Photographs of the arms: For further assessment of lymphedema, we will take
photographs of your arms at the beginning and after 15 months, which takes
about 2 minutes.
- Assessment of lymphedema: Your investigator and you should also independently
rate the aesthetics of the arm using the following 4 options: excellent, good,
normal and poor. This should take no more than 3 minutes.

Expected benefit:
- It may be that by participating in the study, conservative therapy will be
carried out more consistently and successfully, which could lead to an
improvement in your lymphedema.
- Through the regular recording of your quality of life and the consistent,
uniform measurement of lymphedema, it may be possible to react more quickly in
the event of a deterioration of your condition.
- Should you receive surgery, the causes of your lymphedema could be addressed,
which could lead to an improvement in your lymphedema.
- The results of the study could provide patients with an appropriate therapy
recommendation in the future and simplify the reimbursement of costs by health
insurance companies.