Although PBM demonstrated efficacy and safety in a number of randomized clinical trials and meta-analyses23–27, it is rarely used in routine practice. Indeed, treatment is time consuming, equipment is cumbersome and unwieldy; lasers are set with various parameters (wavelength, irradiance, pulse structure, coherence, polarization, energy, fluence) resulting in lack of standardisation. Finally, the procedure is not fully reproducible and operator dependent as the distance from the skin or mucosa is difficult to assess accurately. Thus, the amount of energy delivered cannot be exactly known. CareMin650 is a small and handy device allowing reproducible and accurately controlled delivery of light thanks to direct application of lightning tissue on skin and mucosa. This study aimed at evaluating its feasibility and safety in as many situations as possible, leading to inclusion of 4 subgroups of patients, who underwent applications of pads on mucosa and/or skin, on intact or damaged tissues. The study was performed at highly experienced radiotherapy sites. Characteristics of radiotherapy reflect usual practice with IMRT/VMAT being used in all H&NC patients while one half of patients with BC received RT-3D. Duration, total dose and dose per fraction are consistent with current recommendations. The percentage of patients receiving concomitant chemotherapy was quite low (33%) but not unusual.
The study protocol recommended at least 3 sessions per week, ideally 5. Compliance to treatment was good with a median number of 3.88 sessions per week, which suggests that CareMin650 therapy is feasible even in sites with high patient flow. Indeed, the device is easy to use as the operator only needs to select a dose and the lightbox automatically calculates the duration of application required to deliver this dose. Therefore, application can be performed by any healthcare professional who has been properly trained. In this study, physicians, residents, nurses, radiologic technologists or CRAs were in charge of device utilization.
PBM is known to have good local tolerance6,23. However, a possible concern with CareMin650 was that direct contact of a pad on skin or mucosa could provoke pain or irritation, especially in case of pre-existing lesion. Our results show that local tolerance was very good as no device-related adverse event relating to local pain, irritation or unpleasant feelings has been reported during 1,312 sessions. In particular, all patients from cohort A2 reported that application was not painful, and overall, only 3 patients (4.7%) declared that the application was rather painful and provoked discomfort. Concerns on risks of PBM-related proliferation of tumor cells have been raised and extensively debated due to conflicting in vitro data. However, the use of PBM for more than 30 years, the increasing number of published data in OM prevention in H&NC and SCT patients suggest that PBM does not influence tumor or treatment outcomes and overall survival28. Data in H&NC patients treated with LLLT during RT without prior surgery and long-term follow-up are very reassuring7. Specific evaluation of CareMin650 in an in vitro study showed that irradiated cancer cells do not proliferate when illuminated29.
The study was not designed to demonstrate efficacy. However, preliminary findings can be observed. Only one case of grade 3 RD occurred in the preventive cohorts, and it was diagnosed after the end of RT, therefore did not occur during CareMin650 treatment.
In H&NC patients, grade 3 OM occurred in 4 cases (23.5%), which is lower than reported in the literature, as incidence is usually around 50% and in any case, always exceeds 30% in the absence of efficacious preventive treatement1,3. Importantly, these 4 cases occurred at the same investigational site, among 5 patients included. This discrepancy between sites could be explained by several hypotheses. First, a high variability has been shown in the grading of OM lesions using CTCAEv3 criteria, with discordance rates of 34% between local investigators and central review30. In our study, lesions were graded locally, and no training had been implemented at the beginning of the study to standardize grading. Thus, a very likely explanation lies in the variable analysis of lesions across sites, although grading was to be performed by a physician. The choice of CTCAEv3 for grading had been made because it was considered more accurate than WHO grading scale or CTCAEv5. However, it is also more difficult to use and the distinction between grade 2 and 3 appears very difficult and subject to investigator’s interpretation. Moreover, the choice of grading scale can influence the results. In our study, among patients with food intake limitations, only 3 had G3 OM; therefore, using WHO grading scale, the number of patients with G3 OM lesions would probably have been 3. Second, it has been observed that some lesions were reported late, although symptoms suggesting OM had been described days or weeks earlier, leading to delay in dose increase. This highlights the importance of early detection of lesions with dose increase to 6J/cm2 as soon as a G1 lesion appears. Finally, differences in patients’ population might partly explain a higher incidence of severe lesions, for example different exposures to tobacco and alcohol in one site (North of France) compared to others. Unfortunately, alcohol consumption and smoking status were not recorded in this study. In the ITT population, 2 additional patients developed G3 OM lesions. Both had started CareMin650 several days after the start of RT, suggesting that starting PBM on day 1 of RT is probably key for prevention of OM. No conclusion can be drawn on the effects of CareMin650 in curative settings at this point, due to the small sample size. However, it seems that lesions were stabilized or improved in most cases, although treatment started at grade 2 or 3 in 27% of cases. Finally, safety and efficacy are not the only criteria for a therapy to be implemented in clinical practice. It has to be acceptable for patients and healthcare professionals. In this study, patients’ and users’ questionnaires showed the high rate of satisfaction towards the device.
This study has limitations. It was not a randomized controlled trial, so that no conclusion can be drawn on efficacy. As already mentioned, no standardization training for grading had been performed which raises questions on consistency across investigators. Some data are lacking to better interpret the results, such as smoking habits or alcohol consumption. Finally, the size of each cohort was low, especially in curative settings. Recruitment turned out to be easier in cohorts A1 and B1 that were almost completed when the covid-19 pandemic started. At this time, inclusions were put on hold and ongoing treatments were interrupted, leading to a high number of early study discontinuations. Inclusions resumed after 3 months, in some but not all sites, at a very low rate and it was eventually decided to stop the study as the overall target had been reached, despite the imbalance between cohorts.