Radiotherapy for patients with Ledderhose disease: Long-term effects, side effects and patient-rated outcome

M.N

Ledderhose disease, also called plantar fibromatosis, is a benign hyperproliferative disease of the plantar fascia and was first described by Georg Ledderhose in 1897 [1]. The disease is characterized by the formation of nodules and/or cords under the sole of the foot, often located on the medial and central bands of the plantar fascia [2][3][4]. These nodules can be asymptomatic, though patients may experience some discomfort [4]. The discomfort can vary in intensity from slight tenderness to severe pain and can appear during activity as well as while at rest. With disease progression, the symptoms can lead to functional disability and may have a negative impact on quality of life. Ledderhose disease is associated with Dupuytren's-and Peyronie's disease, but the exact etiology and prevalence are not yet understood [5][6][7][8].
Several treatment options for Ledderhose disease are offered, such as surgery, radiotherapy, extracorporeal shock wave therapy, cortisone injections, orthotics and shoe modifications. However, the level of scientific evidence for efficacy of these options varies [2][3][4]8]. Surgery might be an effective option, especially for severe cases, but it cannot prevent the recurrence and often leaves painful scars and other complications [8]. Only three clinical retrospective studies have investigated the efficacy of radiotherapy for Ledderhose disease (Table 1), all with relatively short term follow up [9][10][11]. In the first two studies, 33 and 36 feet were irradiated in 24 and 25 patients respectively. After a median follow-up of 23 and 38 months, no disease progression was seen and pain reduction or disappearance in 60% of patients was observed. Minimal side effects were reported, such as erythema and skin dryness. The third study evaluated the effect of electron radiotherapy for Ledderhose as well as Dupuytren's disease. A total of 33 patients were included (60 hand/feet). After a median follow-up of 31 months, 80% of patients experienced a decrease in complaints and 94% reported an overall success with radiotherapy, defined as a report from the patient whether they felt the treatment had been successful or not. No grade 2 side-effects were reported in this study.
However, less is known about the long-term outcome of radiotherapy for Ledderhose disease, especially from patients' perspective. Therefore, we conducted a cross-sectional study to investigate the long-term effects of radiotherapy in a cohort of patients treated for Ledderhose disease.

Patients
The patient population was composed of a consecutive series of all patients with Ledderhose disease who were treated with radiotherapy at the University Medical Centre Groningen between 2008 and 2017. Only patients who were at minimum 2 years following completion of radiotherapy were approached by mail in 2019 to participate in this cross-sectional study (NCT04229147). Approval for the study was obtained from the UMCG institutional ethical review-board (METc 2019/203) and all patients provided written informed consent.

Radiotherapy
Radiotherapy was performed using orthovolt (150 kV) or electrons. Radiation with electrons was done with 8 or 10 MeV, depending on nodule thickness. Two separate courses of five daily fractions of 3 Gy each were administered to a total dose of 30 Gy. The interval between the two courses was around 10 weeks.
Patients were positioned prone with their feet in knee support with the plantar surface facing up. The Ledderhose nodules and radiation field were marked on the soles of the feet by the radiation-oncologist. The following margins were used: 2.5 cm in distal-proximal direction and 1.5 cm in lateral-medial direction ( Fig. 1). For electrons, an individually custom lead mould of at least 10 mm thick was made to irradiate only the target area and to protect the rest of the body for receiving radiation.  Long-term effects of radiotherapy for Ledderhose disease

Data collection
Data collection started after receipt of a completed informed consent letter which was mailed to the patients together with a patient information leaflet. Patient and treatment characteristics were collected through MOSAIQ Ò , the patient management information system of Elekta, used at our department. Information on pain from Ledderhose disease, quality of life, patients' levels of satisfaction and side effects of radiotherapy was collected using questionnaires that were mailed to the patients and then filled out and returned by the patients.
The validated BPI was used to assess how much pain from Ledderhose disease interfered with seven daily activities -including general activity, mood, walking, work, relations with others, sleep and enjoyment of life -during the 24-hours prior to completing the questionnaires. For each activity the level of interference was scored using a numeric rating scale from 0 to 10 (no interference to complete interference). Overall pain interference was scored as the mean of the seven interference items.
The validated EURO-QOL-5D-5L consists of a descriptive system with five domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, with five answer levels on each domain. Domain scores were converted into a single summary index score, representing the societal perspective on quality of life. As well as the descriptive system with five domains, the EURO-QOL-5D-5L also contains a visual analogue scale ranging from 0 to 100 (worst to best imaginable health state), representing patients' perspective on quality of life. For both perspectives, higher scores indicate a better quality of life. Scores were compared with EURO-QOL-5D-5L reference values from the Dutch general population in the same age range [12].
The LedRad-LTE questionnaire is a non-validated custom-made questionnaire that contains questions about patients' levels of satisfaction with the effect of the radiotherapy (very satisfied to very unsatisfied), evaluation of the treatment burden (not burdensome to very burdensome), side-effects of radiotherapy (such as erythema, dryness of the skin and oedema of the foot), current status of the disease according to the patient, pain from Ledderhose disease before start of radiotherapy and current pain (both collected at time of completing questionnaires). Pain scores were obtained using a numeric rating scale from 0 to 10, where 0 is no pain and 10 is excruciating pain.

Statistical analysis
A complete pain response was a current pain score of 0 points together with a decrease of the initial pain score by at least two points. A partial pain response was defined as a current pain score of at least 1 point together with a decrease of the initial pain score by at least two points. No change in pain was defined as one or zero pain score point change in either direction from the initial pain score. Progressive pain was defined as an increase in the initial pain score of at least two points [13].
Follow-up time was defined as time between last day of radiation and completion of questionnaires and expressed in months.
Sub-analyses were performed to investigate the effect of several factors on outcome variables, such as gender (males versus females), time after completion of radiotherapy (<4.10 years versus 4.10 years; based on median of 4.10 years), age at end of radiotherapy (<56.42 years versus 56.42 years; based on median of 56.42 years) and surgery prior to radiotherapy (no surgery versus surgery).
All data were analysed using the statistical package SPSS for Windows 23.0 (SPSS Inc, Chicago, IL, USA). Descriptive data are given as mean (±standard deviation, SD) or median (range). All tests were two-tailed with 0.05 as level of significance.

Results
In total, 82 patients were identified as potential participants for this study and invited to participate. Ultimately, 85% (71 patients) consented to participate. Of these, two patients could not be reached to complete the questionnaires, one patient was wrongly included (treated for verruca vulgaris of the right foot instead of for Ledderhose disease), and one patient withdrew consent prior to completing the questionnaires. Therefore, questionnaires of 67 patients (28 men and 39 women) were available for this analysis. Median follow-up time was 49 months (range: 24-132 months). Mean age at end of radiotherapy was 55 years (SD: 9.6 years). Forty patients (60%) also suffered from Dupuytren's disease and four male patients (14%) from Peyronie's disease. Fifty percent of patients reported a positive family history of Ledderhose-, Dupuytren's-and/or Peyronie's disease.
The 67 included patients together comprised 102 treated feet; 20 patients were treated solely on the left foot, 12 on the right foot and 35 patients on both feet. Nine feet were treated with orthovolt and 93 feet with electrons. One patient was re-irradiated on both feet due to new nodules located outside the previous given radiation field. Thirteen patients (14 feet) underwent surgery for Ledderhose disease prior to the radiotherapy. None of the included patients received surgery after radiotherapy.
The mean of the retrospectively collected pain score for all feet before radiotherapy was 5.7 (SD: 2.5) and the mean of the followup pain score for all feet was 1.7 (SD: 2.1) (p < 0.001) ( Fig. 2A). A complete pain response was reported in 42 feet (41.2%), a partial pain response in 38 feet (37.3%) and no change in 22 feet (21.5%). There was no instance of progressive pain (Fig. 3A). The mean of the pain interference score was 1.3 (SD: 1.8). Statistically significant higher pain scores and lower pain responses for females were found compared to males (Figs. 2B and 3B). For the other factors (time after completion of radiotherapy, age at end of radiotherapy and surgery prior to radiotherapy), no effect on pain scores and pain responses was found.
A total of 64 patients completed the EURO-QOL-5D-5L questionnaire ( Table 2). The mean age of these patients was 59.8 years (SD: 9.7 years). The mean of the score for societal perspective on QoL was 0.856 (SD: 0.130) and the mean of the score for patients' perspective on QoL 82.3 (SD: 14.5). Reference values of the Dutch general population in the same age category (50-60 years) were 0.857 (SD: 0.183) and 80.6, respectively. No significant effect of any of the factors from the sub-analyses was found.
Two residual long-term side effects were reported: dryness of the skin (n = 10, 15%) and erythema (n = 2, 3%). Nine patients (26%), reporting on presence of dryness, were in the cohort of 34 patients who were more than 4.10 years after end of treatment (p = 0.05). Six of the 14 feet (43%) which received surgery prior to radiotherapy suffered from dryness of the skin at time of assessment compared to 9 of 88 feet (10%) which did not receive surgery prior to radiotherapy.
A total of 69% of patients reported a permanent positive effect of the radiotherapy on pain and 78% of patients were satisfied with the effect of the treatment. Fifty-seven percent of the patients considered the treatment not burdensome. A statistically significant difference was found between sexes concerning the intensity of   None of the differences between the scores within a factor were statistically significant. Abbreviations: RT: radiotherapy; yrs: years.
Long-term effects of radiotherapy for Ledderhose disease treatment: almost 57% of females found the treatment somewhat burdensome or burdensome compared to 25% of males (p < 0.05).
No differences on the outcomes were found between the feet treated with orthovolt and the feet treated with electrons.

Discussion
To the best of our knowledge, this is the largest study with the longest follow-up to investigate the long-term effects of radiotherapy in patients with Ledderhose disease. Our results show that the previously reported shorter-term pain relief after radiotherapy for Ledderhose disease sustains. Quality of life is comparable to the reference population. Patient satisfaction with the outcome of radiotherapy is high and side effects are minimal.
The patient's perspective is arguably the most important item when evaluating the effect of a treatment. The high level of satisfaction with the effect of radiotherapy in our patient cohort is comparable to the short-term levels of satisfaction reported in previous studies (Table 1) [9][10][11]. In addition, evaluating the level of satisfaction with treatment effect, we also evaluated patient's perspective on treatment burden. This was not reported in previous studies. It should, however, be born in mind that we collected this data retrospectively and recall bias might be an issue. Therefore, we suggest it is valuable to evaluate patient's perspective on treatment burden immediately during treatment, in order to be able to ascertain whether the efforts to undergo the treatment ultimately outweigh its results. In this study, because intensity of treatment was mainly considered not burdensome and levels of satisfaction with treatment effect were high, we conclude, despite the retrospective character of the data collection, that the achieved results outweighed the efforts.
Dryness of the skin was the most reported residual side-effect of this study. It was reported in 15% of patients, which is comparable to the percentages found in the three previous studies (Table 1) [9][10][11]. Dryness of the skin is a common side effect of radiotherapy, especially in breast cancer [14]. In the long term, it might have a negative effect on physical and mental wellbeing [14]. Skin dryness from radiotherapy for Ledderhose disease seems to persist over time, as the residual dryness was reported more often in the patients who were more than 4 years after end of treatment. Therefore, we suggest including the evaluation of skin dryness in the follow-up and, when present, discuss with patients whether there is an impact on wellbeing and if any treatment is needed.
We found several differences between men and women: compared to male patients, females reported significantly higher initial and follow-up pain scores, significantly higher pain interference score and significantly lower pain response scores (complete pain response 30% in females vs. 56% in males). Finally, a significant difference was found concerning the perception of the treatment burden: females found radiotherapy more burdensome than males. In previous studies, no differences in pain scores and pain responses between men and women were described [9][10][11]. In previous literature it was found that gender is an important factor in response to pain [15]. In this regard, it should be emphasized that evaluating the effect of treatment on pain is complex and may be affected by several mechanisms, factors (social, biological and cultural) and their interactions [15].
The risk of developing radiation-induced cancer after radiotherapy for Ledderhose disease within the area of the sole of the foot, where high and low dose radiation was received, is very small, being estimated at 0.02% [16,17]. This risk is predominantly of skin cancer or soft tissue sarcoma. Radiation-induced skin cancer has only been described once for a patient treated at young age with radiotherapy for palmar hyperhidrosis [18]. To the best of our knowledge, it has not been reported in patients treated with radio-therapy for Ledderhose disease. Despite the very low incidence, we suggest discussing this risk with patients during first consultation.
This study has three limitations. The first is its retrospective design; the pain score prior to treatment was collected at time of completing the questionnaires, where recall bias might be an issue. It is recommended that pain scores are obtained during all patient visits, with the first consultation as a starting point. Pain scores can easily be obtained with the numeric rating scale (NRS), which is a valid and reliable scale [19]. Because we collected the pain score prior to treatment retrospectively, this might either over-or underestimate the real effect of radiotherapy on pain. The second limitation is that the natural course of Ledderhose disease could not be evaluated in a control group. Preferably, the effect of radiotherapy should be evaluated in a randomized controlled study, which is currently underway. The third limitation is the duration of the follow-up. Although it is the longest follow-up, so far, for patients with Ledderhose disease treated with radiotherapy, it might still be too short considering the life expectancy of this patient population. Therefore, in a prospective randomized controlled study it should be considered to include a follow-up lasting for decennia or preferably life lasting.

Conclusions
The results of this cross-sectional study suggest that radiotherapy for Ledderhose disease results in long-term pain reduction in most patients. Radiotherapy is well tolerated, leaves patients satisfied, and the resulting quality of life of patients is comparable to the reference population. However, more prospective research, with a long-term follow-up, is needed to evaluate the definitive effect of radiotherapy for Ledderhose disease.

Funding statement
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability statement
Research data are stored in an institutional repository and will be shared upon request to the corresponding authors.

Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.M.N. Werker is member of SERB of Fidia Ltd, Milan. The other authors declare that they do not have any known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.