Photodermatology, Photoimmunology & Photomedicine
ORIGINAL ARTICLE
Narrow-band UVB phototherapy for management of oral chronic graft-versus-host disease Nathaniel Treister1, Shuli Li2, Mark A Lerman1, Stephanie Lee3 & Robert Soiffer4
1 Division of Oral Medicine and Dentistry, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA. 2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. 3 Clinical Research Division, Fred Hutchinson Cancer Research Institute, Seattle, WA, USA. 4 Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, USA.
Key words: graft-versus-host disease; oral mucosa; phototherapy
Correspondence: Dr Nathaniel S. Treister, D.M.D., D.M.Sc., Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, 1620 Tremont Street, 3rd Floor, Boston, MA 02120, USA. Tel: +61 7732 6570 Fax: +61 7232 8970 e-mail:
[email protected] ABSTRACT Objectives Oral chronic graft-versus-host disease (cGVHD) is a debilitating complication following allogeneic hematopoietic cell transplantation. The objective of this study was to evaluate the safety and efficacy of intraoral narrow-band ultraviolet B (NB-UVB) phototherapy in the management of oral cGVHD. Methods Patients with oral cGVHD were treated using a custom NB-UVB unit for a course of 24 phototherapy sessions. Treatments were initiated at 50 mJ/cm2 and increased by 10% at each visit unless toxicity was noted. Toxicity and response were assessed weekly. Results Eleven patients received a median of 22 (range 4–39) NB-UVB treatments; 5 patients completed 24 treatments and elected to receive a median of 7 additional treatments. Median symptom scores (0–10) for sensitivity, pain, and dryness at baseline/end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively. Taking into account all patient-reported outcomes, 7/11 patients had improvement and 2/11 worsened. At least partial improvement was reported in 8/11 patients with none reporting worsening. Overtreatment occurred in 10/11 patients with all graded mild or moderate and resolving in 1–2 days. Conclusions Intraoral NB-UVB may be effective for management of refractory oral cGVHD. Further optimization of treatment parameters, as well as minimal erythema dose testing, and inclusion of a control arm are necessary in the consideration of future studies.
Accepted for publication: 10 September 2014
Photodermatology Photoimmunology Photomedicine 2015; 31: 75–82 Conflict of interest: The authors declare no conflicts of interest.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12141
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Oral chronic graft-versus-host disease (cGVHD) is a frequent and potentially debilitating complication following allogeneic hematopoietic cell transplantation (1). The hallmark clinical manifestation of oral cGVHD is lichenoid mucosal inflammation, characterized by hyperkeratotic reticulations and plaques, erythema, and ulcers that can affect all intraoral surfaces (2). Symptoms include oral pain, sensitivity, and reduced mouth opening, contributing to compromised oral function, limited oral intake, and diminished quality of life (3, 4). Intensive topical immunosuppressive therapy (IST) with high-potency corticosteroids and tacrolimus is the mainstay of effective management for symptomatic patients as both a primary therapy in patients with disease limited to the mouth and an ancillary therapy in those with more extensive cGVHD (e.g. skin, liver, eyes) (5). Despite the overall effectiveness of oral topical IST, shortcomings include the need for frequent dosing and infectious complications. Because responses are variable, there continues to be a need for novel and alternative therapies for management of oral cGVHD. A limited number of case reports and small case series have reported the use of intraoral ultraviolet (UV) lightbased phototherapy, including both psoralen-activated UVA (PUVA, 320–400 nm) and broadband UVB (BBUVB, 290–320 nm), for the management of oral cGVHD (6–9). The potential clinical benefits of UV-based phototherapy are that it is believed to be relatively safe, can be applied to locally affected areas, and may be effective when other treatments, including systemic immunosuppressive medications, have failed (10, 11). The mechanism of action appears to be based on a combination of factors including interference with antigen presentation, diminished production of pro-inflammatory cytokines, and inactivation and/or suppression of T lymphocytes (8). None of the previous reports of phototherapy for oral cGVHD evaluated narrow-band UVB (NB-UVB, 311– 313 nm), which has several theoretical advantages compared with PUVA and BB-UVB including shorter
a
treatment times, the ability to treat without prior administration of a photosensitizing agent, and overall fewer reported complications (11). The objective of this study was to evaluate the safety and efficacy of intraoral NB-UVB phototherapy in the management of oral cGVHD.
METHODS Subjects and eligibility Patients with symptomatic oral cGVHD were recruited from the pediatric (≥ 4 years old) and adult hematology/ oncology clinics at Dana-Farber Cancer Institute, Boston, MA, from August 2006 until September 2008. Patients had to be on a stable immunosuppressive regimen (systemic and topical) that included dexamethasone solution (0.1 mg/ml) oral rinses for 4 weeks prior to study enrollment. Patients being treated with extracorporeal photopheresis were excluded. All patients signed informed consent and all study visits and phototherapy treatments were conducted in the Division of Oral Medicine and Dentistry outpatient clinic at Brigham and Women’s Hospital, Boston, MA. This study was approved by the Dana-Farber/ Harvard Cancer Center’s Office for Human Research Subjects (ClinicalTrials.gov #NCT00374257).
Phototherapy device Phototherapy treatments were delivered using a custom engineered NB-UVB unit that was designed specifically for intraoral use (National Biological Corporation, Twinsburg, OH, USA; Fig. 1). The unit consisted of a power source with timer and a wand-like handpiece fitted with a commercial Philips TL-01/9W PL-S lamp (Amsterdam, The Netherlands) producing UV energy in the ‘narrow-band’ wavelength of 311–313 nm, with an energy output of 3.5 mW/cm2. Energy output was assessed on a regular basis using a National Biological Corporation 500C UVB meter. Electrical tape and an adjustable sliding shield
b Fig. 1. Intraoral narrow-band ultraviolet B NB-UVB device. (a) The unit consists of a base unit and wand including the NB-UVB bulb and blocking mechanism (red tape) including control unit and wand; (b) during a treatment session with the lips protected while exposing the tongue dorsum and palate.
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were used to block the portion of the lamp that was not inside of the oral cavity to avoid exposure of the skin of the face and to block the lips to prevent overexposure (Fig. 1). Both the operator and subjects wore UVBblocking protective eyewear (National Biological Corporation) during all treatment sessions. Disposable plastic barrier sleeves that allowed full transmission of NB-UVB while covering the lamp surface were used for infection control and the unit was disinfected with antimicrobial wipes after each use.
Treatment protocol Subjects were treated for a total of 24 phototherapy sessions on either a twice a week (12 weeks) or three times a week (8 weeks) schedule according to patient preference. Each treatment session consisted of three consecutive exposures, with the lamp first placed between (1) the left buccal mucosa and left ventrolateral tongue, then (2) the right buccal mucosa and right ventrolateral tongue, then (3) the tongue dorsum and palate. The sliding shield was used to block exposure to the labial mucosa and lips during the first two exposures of every treatment session. Treatments were initiated at 50 mJ/cm2 and increased by 10% (rounded to the nearest multiple of 5) at each subsequent visit unless toxicity was noted. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria (version 3.0) at every visit prior to delivery of phototherapy. Toxicity was defined as localized increased sensitivity or a ‘burnt’ sensation, with or without clinically evident associated erythema/ulceration that was not attributed to existing oral cGVHD. In the case of toxicity of any grade, treatments were held until the mouth symptoms (attributed to toxicity) were resolved, with treatment resuming at a 20% reduced dose followed by the same dose escalation protocol. In case of a repeat episode of toxicity at the same dose, the next lower tolerated dose was continued without further increases. Patients experiencing unacceptable toxicity were taken off study. Missed visits were permitted, but any subject missing an entire week of treatment was required to resume the treatment protocol at the starting dose. A detailed treatment log was maintained for each subject. Patients who experienced a response and felt that they were benefitting clinically were permitted to continue therapy beyond the primary 24 session protocol. The maximum dose achieved at the end of the study period was continued on the same treatment schedule until oral cGVHD was stable or resolved, at which point treatment was reduced to once weekly at the same dose. Subjects were Photodermatol Photoimmunol Photomed 2015; 31: 75–82 ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
taken off study if a period of 2 weeks lapsed without a treatment, and in the case of recurrence of symptoms, subjects were permitted to restart phototherapy according to the initial protocol for an additional 24 treatments.
Oral cGVHD assessments Oral cGVHD was assessed at baseline and weekly throughout the study period using both clinician- and patientassessed instruments. These included the National Institutes of Health (NIH) severity score (0–3, clinician assessed), NIH oral mucosal score (0–15, clinician assessed), and NIH oral symptom scores (pain, sensitivity, dryness; 0–10, patient assessed) (12, 13). Subjects were also queried on limitations in eating due to oral cGVHD (0–10), their level of comfort during phototherapy sessions, convenience of phototherapy, and global improvement in the mouth since starting phototherapy (0–10, ‘5’ = unchanged).
Statistical analysis Given the small sample size, the analysis was primarily descriptive. With the intent of summarizing overall treatment effect, we focused on analysis of baseline scores and scores at the end of therapy. While noting that the number of visits varied among patients, the end-of-therapy measurements for most were representative of their overall trend.
RESULTS Patient characteristics Eleven patients were treated with intraoral NB-UVB for management of oral cGVHD during the study period (Table 1). Patients developed cGVHD at a median of 6 months post-transplantation, with the majority (72.3%) having received matched unrelated donor grafts. IST was largely stable during the study period, with the daily prednisone dose tapered or discontinued in seven patients, and topical therapy discontinued in four patients.
Phototherapy summary Intraoral NB-UVB phototherapy was initiated at a median of 8 months post-transplantation. Patients received a median of 22 NB-UVB phototherapy treatments (range 4–39; Table 2). Five patients (5/11, 45%) completed the full 24 treatment protocol; all elected to continue therapy, receiving a median of 7 additional treatments (range 1–39). The six patients that did not complete the protocol 77
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Table 1. Characteristics of the eleven patients treated with intraoral NB-UVB phototherapy n = 11 Median age (range) Male sex, n (%) Conditioning, n (%) Myeloablative Non-myeloablative Donor type, n (%) Matched unrelated Matched related Median time to cGVHD (months, range) cGVHD NIH classification, n (%) De novo Progressive Quiescent Median number of systemic therapies for cGVHD at time of initiation of phototherapy (range) Median time post-transplant (months, range) to initiation of phototherapy
46 (27–73) 10 (90.9) 7 (63.6) 4 (36.4) 8 (72.7) 3 (27.3) 6 (4, 31) 5 (45.5) 4 (36.3) 2 (18.2) 1 (0, 4)
8 (4, 34)
cGVHD, chronic graft-versus-host disease; NB-UVB, narrow-band ultraviolet B; NIH, National Institutes of Health.
Table 2. Summary of phototherapy treatments Case number 1 2 3 4 5 6 7 8 9 10 11
Number of treatments 17 37 4 30 63 6 22 25 6 30 12
Median dose (range) 65 (50–150) 55 (50–100) 62.5 (50–75) 75 (50–100) 75 (50–95) 70 (50–75) 65 (50–75) 70 (45–85) 52.5 (50–60) 80 (50–90) 52.5 (40–65)
Total cumulative dose (mJ/cm2) 1200 2210 250 2330 4605 375 1385 1680 320 2185 635
withdrew primarily because of perceived lack of benefit and inconvenience. No discomfort was reported during (at the time of) any of the phototherapy treatments (data not shown).
Oral cGVHD activity Oral cGVHD activity was assessed by summarizing the measurements at baseline and on the last day of phototherapy (Table 3). The median severity score (0–3) 78
at baseline and at the end of therapy was 2, with four patients improving, two worsening, and five unchanged. The median symptom scores for sensitivity, pain, and dryness at baseline and at the end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively (Fig. 2). Taking into account all patient-reported outcomes, 7/11 patients had improvement (defined by a decrease from baseline of ≥ 3 points in at least one of the three measures) and 2 patients worsened (defined by an increase from baseline of ≥ 3 points in any of the three measures). Of the four cases who did not improve according to any of the patient-reported measures (Fig. 2; Cases 3, 4, 7, and 9), one reported global improvement and three cases reported no change (Table 3). In contrast, all seven patients who improved on at least one measurement in Figure 2 reported global improvement (P value = 0.024). With respect to sensitivity (often the primary driver of oral cGVHD therapy), 5/11 patients improved and no patients worsened. At least partial overall improvement (≤ 4 on 0–10 scale) at the end of protocol therapy was reported in 8/11 patients, with 3/11 unchanged (score of ‘5’ on 0–10 scale) and no patients reporting a worsening of oral symptoms (i.e. score ≥ 6). With respect to the total mucosal scores (0–15 composite score), five patients improved (decrease of 1–7 points), two were stable, and four worsened (increase of 1–5 points). When limiting the analysis to the five patients that completed the full treatment protocol (24 treatments, not including continuing therapy), sensitivity improved in three patients and was stable in two patients, and four reported overall improvement and one reported no change.
Toxicities and late complications There were 36 reported episodes of toxicity in 10/11 (91%) patients, with a median of four instances per patient (range 1–6; Table 4). Patients reported a sensation as if they had been burned (e.g. from eating or drinking something that was too hot) that developed within 12–24 h of phototherapy, with generalized tenderness and hypersensitivity that in many cases corresponded to localized mucosal erythema and/or ulceration. In some cases, toxicity was difficult to assess because of preexisting cGVHD mucosal changes and was attributed to overtreatment due to the onset of symptoms within 24 h of receiving oral phototherapy. The median cumulative dose at which toxicity developed was 615 mJ/cm2, with individual doses (after which toxicity was reported) ranging from 40 to 150 mJ/cm2. The majority of toxicity events were graded as mild and none higher than moderate; all resolved within 1–2 days without intervention. Photodermatol Photoimmunol Photomed 2015; 31: 75–82 ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Table 3. Summary of oral cGVHD disease activity according to NIH oral cavity stage (severity score), oral mucosal score (including component scores), and global improvement (overall assessment of response according to the subject) Case
1 2 3 4 5 6 7 8 9 10 11
Stage
Lichenoid
Erythema
Ulceration
Mucoceles
Total mucosal score
Global improvement 5 = no change > 5 = worse < 5 = improved 4 4 5 5 1 3 5 4 4 0 3
Visit A
Visit B
Visit A
Visit B
Visit A
Visit B
Visit A
Visit B
Visit A
Visit B
Visit A
Visit B
2 2 3 2 2 2 2 2 3 2 2
2 1 3 2 1 1 2 3 3 1 3
2 3 2 1 1 3 1 2 2 1 3
2 1 2 2 1 2 1 1 2 1 2
2 1 1 1 1 1 1 2 1 2 1
1 0 1 2 1 1 1 1 2 1 1
3 3 3 0 3 3 0 3 3 3 0
3 0 3 3 3 0 3 3 3 0 3
0 1 0 0 0 0 0 0 1 0 1
0 0 0 0 1 0 0 1 0 0 2
7 8 6 2 5 7 2 7 7 6 5
6 1 6 7 6 3 5 6 7 2 8
Visit A = initial/baseline visit; Visit B = final visit/end of therapy. cGVHD, chronic graft-versus-host disease; NIH, National Institutes of Health.
Squamous cell carcinoma (SCC) of the anterior tongue was diagnosed in Case 8 (1750 mJ/cm2 total dose) approximately 5 years after the last phototherapy treatment. Dysplasia of the buccal mucosa was diagnosed in Case 10 (2185 mJ/cm2 total dose) approximately 5 years following the last phototherapy treatment. Both patients were managed with surgical resection and remain alive at this time. Of the other four known survivors, the follow-up times are 2.0, 2.9, 4.6, and 8.3 years, respectively, and no SCC or dysplasia was noted at the last contact.
DISCUSSION We report our experience using intraoral NB-UVB phototherapy for the management of oral cGVHD. Because of the rigid eligibility criteria and the intensity of the treatment protocol, enrollment was slower than anticipated and the study was closed early. Given the small number of subjects (n = 11), and even smaller number that completed the full treatment protocol (n = 5), and the uncontrolled study design, it is not possible to critically evaluate efficacy of this therapy. Furthermore, cGVHD activity is known to wax and wane over time, such that it is again impossible to absolutely attribute improvement over time to the NB-UVB intervention. However, it does appear that some patients experienced a true therapeutic benefit with improvement in symptom scores and resolution of mucosal inflammation. Despite what were believed to be Photodermatol Photoimmunol Photomed 2015; 31: 75–82 ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Table 4. Summary of phototoxicity events Number of patients experiencing ≥ 1 toxicity Number of toxicity occurrences Toxicity grade, n (%) Mild Moderate Median number of toxicities per patient (range) Median cumulative dose leading to toxicity, mJ/cm2 (range) Dose intensity (mJ/cm2) leading to toxicity, n (%) 40 45 50 55 60 65 70 75 80 85 100 Median number of doses leading to initial toxicity Toxicity attribution, n (%) Definite Possible Probable N/A
10 36 27 (75.0) 9 (25.0) 4 (1, 6) 780 (100, 4525)
1 (2.78) 1 (2.78) 3 (8.34) 3 (8.34) 4 (11.11) 1 (2.78) 5 (13.9) 7 (19.4) 3 (8.34) 3 (8.34) 5 (13.9) 5
4 (11.1) 20 (55.6) 11 (30.6) 1 (0.03)
N/A, not available. 79
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Fig. 2. Oral chronic graft-versus-host disease (cGVHD) symptom scores at baseline and end of therapy. *Indicates score decreased (improved) at least 3 points.
adequate safety measures, toxicity occurred more frequently than anticipated and at times could be difficult to discern from cGVHD-associated signs and symptoms. Despite the fact that all patients with cGVHD are already at significantly increased risk for developing oral cancer, the two patients that developed late complications of oral dysplasia and SCC raise potential concerns regarding longterm safety (14, 15). There have been five previous reports (including a total of 14 patients) that described the use of both PUVA (n = 4) and broad spectrum UVB (n = 1) for the management of oral cGVHD (6–9, 16). Phototherapy was delivered two to four times per week with the dose (in all but one report) incrementally increased from every treatment to every fourth treatment. In two reports, phototherapy was deliv-
ered ‘extraorally’ with the patient’s mouth open against a larger, flat light source that was intended for cutaneous exposure (6, 16). Atkinson et al. described protecting (blocking) the skin and lips and retracting and everting the buccal mucosa on the right (one exposure) and left (one exposure) sides, followed by exposure of the tongue by sticking the tongue out of the mouth (16). Elad et al. described treatment of the gingiva (one exposure), the buccal mucosa and palate (mouth wide open, one exposure), and the tongue (one exposure); there was no specific description of protection of the skin and/or lips (6). The remaining studies described the use of intraorally delivered UVA irradiation using a dental curing light (n = 2) and a custom-engineered bulb delivery system (n = 1). Across all studies, patients received between 3 and 92 phototherapy
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treatments, with the duration of therapy ranging from approximately 1 week to 4 months. There was no consistently used method of assessing response, with all but one study providing descriptions only. Concurrent ISTs and changes in regimens over the treatment periods were generally not described. Regardless, taking into account all reports, responses (partial and complete) were reported collectively in 12/14 patients. There are potential short- and long-term risks associated with the use of intraoral NB-UVB phototherapy in patients with cGVHD. Overtreatment resulting in a burn is well described in the dermatology literature, and a number of safety measures are taken to minimize risk (11). Cutaneous dosing is determined in part by assessing a patient’s skin type (light to dark) and/or testing for a minimal erythema dose (MED), from which a safe and effective starting dose is determined (11). Kuusilehto et al. evaluated the MED (assessed after 24 h) of PUVA, using a topical photosensitizer, for the skin and oral mucosa in 16 healthy Caucasian volunteers (17). The average dose required to induce erythema of the oral mucosa (1.8–4.5 J/ cm2) was on average 2.3 times greater than that for the skin (0.6–1.8 J/cm2); however, the actual clinical findings (e.g. erythema, ulceration, symptoms) were not described. The authors speculated that this difference may be due to the increased epithelial thickness of human oral mucosa compared with skin. We made no attempt to determine an MED of the oral mucosa (or skin) in the current study. Despite an increased risk of skin cancer in patients treated with long-term PUVA therapy, this risk has not been demonstrated in association with NBUVB (18). Given that patients with cGVHD are at a significantly increased risk of developing oral SCC, it is unclear to what extent intraoral NB-UVB may further increase this risk (15). Overtreatment has been described in the prior reports of intraoral phototherapy for oral cGVHD (6–9, 16). Excluding one patient that received only three PUVA treatments (and did not experience toxicity (16)), ‘overtreatment’ was described in 4/13 patients, generally described as a burn sensation with or without associated erythema. In all cases,
overtreatment was described as a single event and did not recur upon further therapy, and only the report by Menillo et al. described holding treatment for 1 week prior to resuming phototherapy (9). In contrast, in the current report, there was a median of two phototoxicity events per patient occurring at doses ranging from 40 to 150 mJ/cm2. Because most subjects enrolled in the protocol had extensive oral cGVHD that frequently included ulcers, it was often challenging to clearly differentiate phototoxicity from underlying cGVHD. From this study, we can at least estimate that the upper tolerated dose of intraoral NB-UVB for oral cGVHD is between 70 and 100 mJ/cm2, suggesting a fairly narrow therapeutic dose range. It appears that the dose escalation protocol utilized in this study was overly aggressive; suggesting that a more gradual increase (e.g. after every third treatment) and a predetermined upper dose limit (e.g. 100 mJ/cm2) would effectively minimize the risk of toxicity. In summary, we report for the first time the use of intraorally delivered NB-UVB phototherapy for the management of refractory oral cGVHD. Using the protocol that we followed, there was greater toxicity than anticipated and responses were variable. A study of MED testing for intraoral NB-UVB phototherapy in both healthy volunteers and patients with oral cGVHD should be conducted before considering further clinical trials. Because of the theoretical carcinogenic risk of NB-UVB exposure, future studies should incorporate long-term safety follow-up.
ACKNOWLEDGMENTS This work was supported by grant CA118953 and the Division of Hematologic Malignancies, Dana-Farber Cancer Institute. We thank Mark Friedman and his colleagues at National Biological Corporation for custom designing and engineering the phototherapy unit. We would also like to thank Lei Zhao and Jennifer Brewer for their assistance with data analysis and manuscript preparation. We finally and most importantly extend our gratitude to our patients for participating in this clinical research protocol.
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