Placebo-Controlled Phase II Randomized Clinical Trial of Photobiomodulation Therapy in Head and Neck Cancer Survivors with Chronic Lymphedema

There are over half a million head and neck cancer (HNC) survivors in the United States. More than two-thirds experience chronic soft tissue swelling (lymphedema) in the head and neck region. Lymphedema not only has adverse cosmetic and psychosocial consequences but can cause a substantial impact on critical functions (e.g., swallowing) and result in decreased range of motion in the jaw, neck, and shoulders. The standard of care for acute or early-stage lymphedema is complete decongestive therapy (CDT). After completion of CDT, 30%-40% of survivors still have clinically evident residual lymphedema that can progress to chronic lymphedema. Currently, there are no proven effective therapies for the treatment of chronic lymphedema. Innovative solutions are needed for the management of this potentially devastating late effect. Photobiomodulation therapy (PBMT) was approved by the FDA in 2006 as a treatment for breast cancerrelated arm lymphedema. Evidence supports that PBMT is a potentially effective treatment for arm lymphedema. No data is available on the effects of PBMT on head and neck lymphedema. We conducted two pilot clinical trials. Results demonstrated the feasibility, acceptability, and preliminary efficacy of PBMT for the treatment of chronic lymphedema in HNC survivors. No adverse events were identified during the trials. Given the promising findings from our pilot trials, we propose to conduct a 5-year, multi-site, triple-blind, placebocontrolled, three-arm parallel, phase II randomized clinical trial (RCT) to further investigate and confirm the positive effects of PBMT on chronic lymphedema in HNC survivors. The goals of the proposed research are to evaluate the effects of PBMT on the severity of external and internal lymphedema; to assess the impact of PBMT on symptom burden, functional impairments, and quality of life; and to collect and biobank peripheral blood samples for future analysis if we observe an improvement in chronic lymphedema and associated symptom burden or functionality with PBMT. In our previous pilot trials, participants received 12 PBMT sessions with follow-up through 8-week post-PBMT. Data demonstrated a plateau in the external lymphedema severity reduction and symptom improvement after cessation of PBMT, suggesting that increased duration of therapy may enhance outcomes. To answer this question, we will evaluate if extending treatment will generate improved outcomes. Thus, patients will be randomized (1:1:1) to ARM A – PBMT12 (12 PBMT sessions plus 6 sham therapy sessions), ARM B – PBMT18 (18 PBMT sessions), or ARM C – placebo (18 sham therapy sessions). We will enroll 150 HNC survivors (50 per arm) from two participating sites. Our primary endpoint is improvement in severity of external lymphedema. Study assessments will be conducted pre-intervention, after 12 sessions, after 18 sessions (end-of-intervention), and 3-, 6-, 9-, and 12-month post-intervention. Successful completion of this trial will provide critical data for designing a subsequent phase III RCT to provide level 1 evidence supporting the effectiveness of PBMT in HNC survivors with chronic lymphedema.