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Supportive care of cancer patients with a self-applied photobiomodulation device: a case series

Purpose Oral mucositis (OM) and prolonged wound healing are common side-effects of cancer treatments. Photobiomodulation (PBM), previously called low-level laser, is currently part of the official guideline for OM prevention. However, all the PBM protocols relate to office-based devices, operated by professional health caregivers, requiring frequent applications. In the following case series, we present our experience with a self-applied consumer home-use PBM device for supportive care. Methods Five patients receiving cancer treatment presented at the clinic (female:male 3:2, 55–76 years old) with OM grade 3/4 (n=2), post-surgical non-healing wounds (n=3), and dermatitis (n=1). The PBM treatment (808 nm, 250 mW peak power, 15KHz, 5 J/min, ray size 4.5×1.0cm2) was self-applied by the patients. The protocol included extra/intra-oral applications, over the wound bed/margins and adjacent lymph nodes. Results The treatment was found effective for resolving OM with rapid pain relief and accelerated healing in post-operative wounds and dermatitis, without reported adverse events. Patients found routine easy to follow and painless, and the protocol was easily integrated as an adjuvant treatment to standard care at the clinic or home while not requiring additional time from the staff. Conclusions Side-effects induced by cancer therapy have a detrimental effect on the patient's well-being and may delay or even prevent the patients from completing treatment regimens. PBM is already an established tool for supportive treatment in cancer patients. The advent of a self-applied personal PBM treatment with easy-to-apply protocols for a variety of side-effects makes this technology an important accessible and safe supportive care option.


Introduction
In cancer therapy, chemotherapy and radiotherapy may damage healthy tissues leading to side-effects, among which oral mucositis (OM) [1] and prolonged wound healing are prominent [2]. OM is characterized by oral mucosal erythema, ulceration, and pain, thus frequently impairing the ability for food intake, and potentially preventing the patient from receiving the full cancer treatment regimen [1]. Prolonged wound healing may lead to postoperative complications in the form of dehiscence and increased incidence of infection, as well as the formation of non-healing chronic wounds and impaired quality of life [2].
Photobiomodulation (PBM), previously termed lowlevel laser therapy, is the application of non-ionizing visible or near-infrared optical radiation to tissue. The photons are absorbed by endogenous chromophores that elicit photochemical events without creating thermal damage [3,4]. PBM is used clinically to accelerate wound healing and reduce inflammation, edema, and pain [3,4] and was shown to affect multiple molecular pathways related to wound healing and to be particularly effective in the acceleration of healing of chronic wounds [5]. In the past 2 decades, PBM has been increasingly used as a new treatment modality in cancer patient supportive care and was suggested for prevention and management of cancer-induced toxicities [6][7][8] without association to long-term risk of malignant transformation, progression, or recurrence [9 , 10]. International guidelines for the prevention of OM using PBM were published by the UK National Institute for Health and Care Excellence (NICE) interventional procedure guidance (IPG615) [11] and by the Multinational Association of Supportive Care in Cancer, and the International Society of Oral Oncology (MASCC/ ISOO) [7,12].
However, the existing data originated from studies using office-based PBM devices at the clinic were operated by professional health caregivers. The requirement for multiple frequent treatment sessions (usually 2 to 5 sessions per week) at the clinic is in many cases not feasible nor convenient for the patients [13] and may also impose a serious health concern for these immunocompromised patients.
In the following case series, we present our experience with an approved (in Israel, Canada, Europe, and Brazil) consumer home-use near-infrared PBM device (B-Cure Laser Pro, Good Energies Ltd., Haifa, Israel). This lightweight, hand-held device was previously shown to be effective for the treatment of peri-implant gingival mucositis [14] and diabetic foot ulcers [15,16]. The energy parameters of the device are 808 nm wavelength, 250 mW peak power (55 mW/cm 2 ), 15KHz, 1.1 J/cm 2 /min, while the ray size is 4.5×1.0cm 2 enabling the simultaneous irradiation of a relatively large area in a short time compared to laser pointers.
We have developed a protocol based on our interpretation of the PBM literature related to the treatment of OM and other cancer-related side-effects [8] combined with our experience in the treatment of non-healing wounds [16], while taking into consideration the technical specifications of the device.
For OM, the protocol includes PBM irradiation intraorally over the tongue and inner epithelial surface of the lips, and extra-orally on the cutaneous surface corresponding to the buccal mucosa, and cervical lymph nodes. For non-healing post-operative wounds and dermatitis, the protocol includes irradiation over the wound bed, wound margins, tunneling wound (an internal channel that extends from the post-operative wound into the subcutaneous tissue), and adjacent lymph nodes.

Aim
Our purpose was to report cases demonstrating a significant improvement following self-applied PBM prophylaxis/ treatment for patients with complications of cancer therapy and to detail the protocol used.

Cases
Here we report 5 patients (3:2 female: male, with an age range of 55-76 years), of which, 2 had OM (grade 3 and 4, according to the World Health Organization [WHO] scale, i.e., oral ulcers were present and only liquid diet is possible, or oral alimentation impossible, respectively ( Fig. 1)), 3 had post-operative wounds (post-Hartmann reconstruction and small bowel resection d e h i s c e n c e ( F i g . 2 ) , n o n -e p i t h e l i a l i z e d p o s themicolectomy abdominal wound, post-total mastectomy seroma wound with tunnel), and one had chemotherapyinduced dermatitis in the groin area (and concomitant OM; (Fig. 3)). The treatments took place during May-August 2018 in 5 consecutive patients that were referred to the clinic and agreed to therapy (additional 2 patients who were presented to the clinic during this period with cancer treatment-related side-effects and were offered to be treated with PBM refused to be treated with this method). The patients' relevant medical background, specific PBM treatment protocols, and responses are summarized in Table 1. The detailed timeline of case #1 is presented in Table 2. This case series was written according to the CARE reporting guidelines [17].

Discussion
In the cases presented, self-applied PBM therapy at the clinic or at home was found effective for resolving OM with rapid relief of related pain, as well as for accelerating healing in post-operative non-healing wounds and dermatitis, with no reported adverse events.
The treatment protocol was followed by the patients after a short explanation without difficulty. The extraoral/over skin treatment that was applied by the patients themselves was not painful and did not require time from the staff. The PBM home-use device itself is hand-held, lightweight, and the instructions are self-explanatory. However, the intra-oral application is not convenient due to the device configuration.
PBM is already part of the official guidelines for the treatment of OM and is routinely used at hematological and oncological clinics [11, 12,18]. Clinical studies also support the use of PBM for other toxicities induced by chemotherapy/radiotherapy including lymphedema, radiodermatitis, osteonecrosis of the jaw, and peripheral neuropathy [7,19,20] as well as oral manifestations of chronic graft versus host disease following allogeneic hematopoietic stem cell transplantation [21,22]. However, all previous reports related to treatments performed by the professional medical team at the clinic. This is the first report to show beneficial effects related to supportive care in cancer patients with a self-applied PBM device. In addition to pain relief and accelerated healing in cases of established OM (case #1 and case #2), this device may also allow a pre-conditioning period as well as convenient at-home prophylaxis treatments as done by patient #2. A personal home treatment enables frequent treatments with a minimal number of additional visits to the hospital which is of high importance with regard to patient's convenience, compliance, and safety, for example, due to the need to restrict the Fig. 1 Oral mucositis. Case #2. Severe oral mucositis (World Health Organization grade 3) on palate and lips (a and b, respectively) that led to halting chemotherapy. White and black arrows indicating palatial and lip lesions. After 5 treatments (c), complete healing of the palate and lips. Patient was then able to continue chemotherapy. For clinical details, see Table 1 Fig. 2 Wound dehiscence. Case #3. Surgical site infection following Hartmann procedure resulted in wound déhiscence (a). Two weeks after the first treatment, full granulation (b), and 1 week later the wound was completely epithelialized (c-d). For clinical details, see Table 1 Fig . 3 Dermatitis. Case #6. Skin irritation in groin area (a). The wound considerably improved after 4 daily photobiomodulation treatments (b) and completely healed within 2 weeks (c). For clinical details, see Table 1 Table  -19) or other potential infection in immunocompromised cancer patients. PBM was shown to be beneficial for acceleration of healing of both acute and chronic wounds [5] based on its ability to enhance the microcirculatory flow [23] and to stimulate the mitochondria energetic state even in stressed conditions [24,25]. Particularly, the PBM protocol (and the same device) used in this study was previously reported to accelerate healing of diabetic foot ulcers [15,16] and to prevent post-laminectomy scar formation when used as a preventive measure [26]. Other protocols were shown to be beneficial for prevention and accelerate healing in cases of wound dehiscence [27,28]. However, dehiscence related to chemotherapy is particularly challenging, and therefore, the beneficial effect presented here warrants special attention.
In summary, side-effects induced by cancer therapy have a detrimental effect on the patient well-being and may delay or even prevent the patients from completing treatment regimens. PBM is already an established tool for prevention of OM. The advent of a self-applied personal PBM treatment with easy to apply protocols for a variety of side-effects makes this technology an important accessible and safe supportive care option. CT chemotherapy, MTX methotrexate, min minute, NRS numerical rating scale, with range of 0 to 10, for self-assessment of pain, NPWT negativepressure wound therapy, OM oral mucositis, ORC oxidized regenerated cellulose, PBM photobiomodulation, R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, RT radiation therapy, Tx treatment, WHO World Health Organization, y.o. year old. *All photobiomodulation treatments were conducted using B-Cure Laser Pro (Good Energies Ltd., Haifa, Israel) with the following parameters: wavelength, 808 nm; power, 250 mW (55.6 mW/cm 2 ); frequency, 15KHz, 1.1 J/cm 2 /min; spot size, 4.5×1.0cm 2 . **Cases #2 and #6 are the same patient