British Association of Dermatologists' guidelines for the management of squamous cell carcinoma in situ (Bowen's disease) 2014.

Abstract

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of squamous cell carcinoma (SCC) in situ (Bowen's disease). The document aims to update and expand on the previous guidelines by (i) offering an appraisal of all relevant literature since January 2006, focusing on any key developments; (ii) addressing important, practical clinical questions relating to the primary guideline objective, i.e. accurate diagnosis and identification of cases and suitable treatment; (iii) providing guideline recommendations and, where appropriate, some health economic considerations; and (iv) discussing potential developments and future directions. The guideline is presented as a detailed review with highlighted recommendations for practical use in the clinic (see section 16), in addition to an updated patient information leaflet [available on the British Association of Dermatologists' (BAD) website, http://www.bad.org.uk]. The guideline also reviews erythroplasia of Queyrat (EQ)/penile intraepithelial neoplasia (PIN) and bowenoid papulosis, which have similar histology and are often diagnosed by dermatologists; however, a detailed therapeutic review of these conditions is beyond the scope of this guideline. This guideline does not offer treatment recommendations for vaginal intraepithelial neoplasia or perianal SCC in situ. The guideline development group consisted of consultant dermatologists. The draft document was circulated to the BAD membership, the British Dermatological Nursing Group (BDNG) and the Primary Care Dermatological Society (PCDS) for comments, and was peer reviewed by the Clinical Standards Unit of the BAD (made up of the Therapy & Guidelines Subcommittee) prior to publication. This set of guidelines has been developed using the British Association of Dermatologists' recommended methodology,1 with reference to the Appraisal of Guidelines Research and Evaluation (AGREE II) instrument (www.agreetrust.org).2 It represents a planned regular update of the previous BAD guidelines for the management of SCC in situ (Bowen's disease).3, 4 Recommendations were developed for implementation in the U.K. National Health Service (NHS) using a process of considered judgement based on the evidence. The PubMed, Medline and Embase databases were searched for meta-analyses, randomized controlled trials (RCTs) and non-RCTs, case series, case reports and open studies involving SCC in situ (Bowen's disease) to September 2013; search terms and strategies are detailed in the Supporting Information. Additional relevant references were also isolated from citations in the reviewed literature, as well as from a specific targeted search for PIN. Each author screened their set of identified titles, and those relevant for first-round inclusion were selected for further scrutiny. The authors then reviewed the abstracts for the shortlisted references, and the full papers of relevant material were obtained; disagreements in the final selections were resolved by discussion within the entire development group. The structure of the 2007 guideline was then discussed and re-evaluated, with headings and subheadings decided; different coauthors were allocated separate subsections. Each coauthor then performed a detailed appraisal of the selected literature, and all subsections were subsequently collated and edited to produce the final guideline. The authors intend that the recommendations and quality of evidence reflect the full evidence base at the time of writing and may be read without the need for reference to earlier versions, although detailed discussion of older studies is not repeated here. It should be recognized that this new version may give disproportionate weight to references to newer publications and therapies. Where there are direct comparisons between therapies, these are generally discussed in the section relating to those deemed to be most efficacious. Recommendations take into account simplicity, cost and healing, as well as the type and validity of the published evidence base; for any treatment, there may be site-specific differences in the recommended option. This document has been prepared on behalf of the BAD and is based on the best data available when the document was prepared. It is recognized that under certain conditions it may be necessary to deviate from the guidelines and that the results of future studies may require some of the recommendations herein to be changed. Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence. The proposed revision for this set of recommendations is scheduled for 2019; where necessary, important interim changes will be updated on the BAD website. Bowen's disease is a form of intraepidermal (in situ) SCC, originally described in 1912,5 although the original lesions, located on sites that were not sun exposed, were possibly arsenic induced. Current practice is to consider Bowen's disease as synonymous with SCC in situ for lesions sited on nongenital areas. In line with reduced use of eponyms, we have used the term squamous cell carcinoma in situ (SCC in situ) throughout this updated guideline. Squamous cell carcinoma in situ typically presents as a well-demarcated, erythematous hyperkeratotic plaque with an irregular border, characterized by full-thickness epidermal dysplasia on histology. An annual incidence of 15 per 100 000 has been suggested in the U.K.6; however, this was based on U.S. data, which may reflect a higher incidence due to greater sun exposure.7 Peak incidence of the disease occurs in the seventh decade of life, and most studies have shown a slight female preponderance.8-11 The majority of studies report that SCC in situ occurs mainly on sun-exposed sites, with more recent studies suggesting the most common site being the head and neck (29–54%)10-13; however, the lower limbs seem to be affected more in women than in men.8, 11, 14 Older, U.K.-based studies have reported that the majority of patients (60–85%) have SCC in situ on the lower legs, which may indicate that the sun exposure pattern is different in countries with lower rates of sunshine.8, 9 Less common variants include pigmented, subungual, periungual, palmar, genital, perianal and verrucous SCC in situ. In routine clinical practice the diagnosis is made on clinical grounds, perhaps with the aid of dermoscopy (showing glomerular vessels and scaling).15-17 If there is diagnostic doubt, or if confirmation is required before proceeding with a certain type of treatment, a punch biopsy can be performed. This is preferable to a curette biopsy, as the full thickness of the epidermis and dermis can be viewed to establish whether there is any invasive disease amounting to a cutaneous SCC. Aetiological factors for SCC in situ include (i) irradiation: ultraviolet radiation (solar, iatrogenic and sunbeds)14, 18 and radiotherapy; (ii) carcinogens: arsenic (lesions may arise in sun-protected areas)19; (iii) immunosuppression: in particular, therapeutic20, 21; (iv) viral: there is an association between human papillomavirus (HPV), especially HPV16, and the development of anogenital SCC in situ,22-24 but this is by no means conditional for its development.25 HPV DNA has been demonstrated in extragenital SCC in situ in varying amounts from 4·8–60%.24, 26-28 It appears that HPV16 may be particularly relevant with regard to development of SCC in situ on the hands and feet; it has been implicated in 60% of palmoplantar and periungual lesions29; and (v) others: chronic injury or dermatoses (such as lupus vulgaris or chronic lupus erythematosus) have been implicated.30 Previous studies have suggested that about 30–50% of subjects with SCC in situ may have previous or subsequent nonmelanoma skin cancer (NMSC), mainly basal cell carcinoma (BCC).18, 31 The NMSC risk after an index SCC in situ is probably similar to the overall risk of NMSC following any index NMSC (3-year overall risk of 35–60%).32 In the study by Jaeger et al.,10 NMSC had a standardized incidence ratio of 4·3, and lip cancer a ratio of 8·2, in patients with SCC in situ (calculated as ratios of observed-to-expected numbers of cancer, derived from cancer registration data in Denmark). These increased risks of further SCC in situ or of other NMSCs probably reflect a common solar aetiology. Most studies suggest a risk of invasive carcinoma of about 3–5% for typical SCC in situ,33, 34 and about 10% for EQ.3 In bowenoid papulosis, invasion is extremely rare.35 Perianal SCC in situ has a higher risk of invasion and recurrence. However, these estimates are drawn from retrospective case series, may be biased by different referral patterns of lesions to different disciplines, and do not take account of subjects with SCC in situ who have either not requested medical advice or who have been treated in primary care. Evaluation of treatment studies of typical SCC in situ is difficult due to potential selection bias in relation to specific forms of treatment. Moreover, healing and clearance rates may vary with body site. Earlier studies used clinical appearance rather than histological assessment to determine the end point of lesion clearance and, in practice, most dermatologists will instigate treatment without first resorting to a biopsy. Even for the same treatment modality, there is difficulty in directly comparing studies due to different lesion site and size, and use/availability of different types of equipment and treatment regimens.36 Retrospective studies in particular may have several inherent problems; in ‘real-world’ treatment of SCC in situ, clinicians may select several different types of treatment,37 with decisions potentially being influenced by several factors, such as lesion size and thickness, equipment available, and the perceived potential for poor wound healing (e.g. at sites such as the lower leg).38 Current U.K. product licences for many of the drugs listed do not include treatment of SCC in situ; all recommendations in this guideline are extrapolated from literature on SCC in situ and knowledge of other neoplastic skin lesions, and are presented on the understanding that neither the authors nor the BAD can formally recommend an unlicensed treatment. Treatments are presented in a sequence that discusses the least invasive and topical therapies first, then surgical approaches, and finally treatments that require more complex or expensive equipment or are not widely available. A summary of advice incorporating these issues, and related to lesion sites and sizes, is provided in Table 1. A recent review of interventions for SCC in situ by the Cochrane Skin Group39 identified nine RCTs, but noted limited data for surgery and topical cream therapies. The review concluded that photodynamic therapy (PDT) using methyl aminolaevulinate (MAL) is an effective treatment, more efficacious than cryotherapy, but not significantly different from topical 5-fluorouracil (FU). PDT using aminolaevulinic acid (ALA) achieved a significantly higher clearance rate than 5-FU, but there was no significant difference in clearance between 5-FU and cryotherapy. In some patients with slowly progressive thin lesions, especially on the lower leg of elderly patients where healing is poor, there is an argument for observation rather than intervention. In these cases use of an emollient (especially one containing urea) can reduce the scaling and make it less obvious (see Appendix 1). Topically applied 5-FU is a well-recognized treatment option for SCC in situ and is commercially available in the U.K. as a 5% cream. Many of the original studies were performed using different concentrations and various regimens. The typical regimen in current clinical use is once- or twice-daily application for 3–4 weeks, repeated if required. There have been a number of good-quality studies in recent years comparing the efficacy of 5-FU with that of PDT. Topical 5-FU cream, applied once daily for 1 week, then twice daily for 3 weeks, was compared with both MAL-PDT and cryotherapy in a large European multicentre RCT.40 At 3 months following the last treatment, 83% of lesions treated by 5-FU showed complete response, compared with 93% with PDT and 86% with cryotherapy, with follow-up rates discussed below. A smaller RCT of 40 patients comparing 5-FU, applied in the same manner and repeated if required, with ALA-PDT showed a 67% response rate, compared with 88% with PDT.41 At 12 months, following two recurrences in patients receiving PDT and six in patients treated with 5-FU, only 48% of patients treated with 5-FU were clear compared with 82% with PDT. A small randomized intrapatient comparative study compared 5-FU, twice daily for 3 weeks, with MAL-PDT in organ transplant recipients (OTRs) with epidermal dysplasia.42 Only five patients had SCC in situ and the baseline data were not equivalent, with the lesions treated with 5-FU being about a third larger than those treated with PDT. Four of the five patients treated with PDT had a complete response at 6 months, with the fifth having a partial response, whereas all five patients treated with 5-FU had only a partial response. Despite this, the difference was nonsignificant once a multiple regression analysis had been performed. Of 406 biopsy-proven SCCs in situ treated at a single centre in the U.S.A. between 1999 and 2003, 24 lesions were treated with 5-FU (the vast majority were treated using surgical techniques).11 Only one lesion recurred after a mean follow-up period of 23·6 months, comparing favourably with the subset of lesions treated by surgery, with three recurrences out of 109 patients following elliptical excision, and two of 83 following Mohs micrographic surgery. These data are similar to those of another follow-up study (26 patients, 2·4–204 months of clinical follow-up) in which recurrences had occurred in only two patients (8%).43 It has been reported that the efficacy of 5-FU may be increased by application under occlusion,44 use of dinitrochlorobenzene as a vehicle,45 iontophoresis46 (to improve follicular penetration) or pretreatment with a laser (to ablate the stratum corneum and thus enhance penetration of 5-FU).47 Imiquimod stimulates both the innate and acquired immune systems, resulting in antitumour and antiviral activity. It is available as a topical 5% cream and has been used to treat SCC in situ, although its licence in the U.K. is only for superficial BCCs, actinic keratoses and genital warts. It is generally well tolerated, but it does cause significant erythema and crusting, so appropriate counselling needs to be given prior to treatment. The best evidence remains a small RCT demonstrating 73% histologically proven resolution with once-daily application for 16 weeks, vs. zero response in the placebo group.48 An interesting observation from the study was that the nonresponders had hyperkeratotic lesions, suggesting that the drug was unable to penetrate the thick keratin layer. An open-label clinical trial on five patients who were deemed unsuitable for surgery used imiquimod once daily, five times a week until the lesions clinically cleared, for up to a maximum of 16 weeks. After 8–12 weeks of treatment, four of the five SCC in situ lesions showed complete clinicopathological resolution, with no recurrence after a mean of 31 months of follow-up.49 Another open study on 16 patients with previously untreated lesions (15 on the lower leg) who used imiquimod once daily for up to 16 weeks reported that 93% (14/15) of patients who completed the study had clinicopathological resolution 6 weeks after the treatment period.50 Five lesions had an area of ≥ 5 cm2. One retrospective study from Texas reported that 86% (42/49) of patients (96% were male) with SCC in situ (11% were genital lesions) treated for ≥ 6 weeks had complete response to topical imiquimod applied once daily for extragenital lesions (mean duration 9 weeks) and every other day for genital lesions.51 Another study from Brazil reported that only 57% of patients (four of seven) with SCC in situ, without any significant comorbidities such as immunosuppression, cleared following a mean of 6·1 weeks of treatment.52 Single cases or small case series suggest that different regimens such as cyclical treatment53 might be useful, and also that imiquimod might be effective for large facial lesions.54 These, along with lower-leg lesions,50 are typically those that pose the greatest therapeutic challenge. Some studies suggest that shorter treatment periods may be adequate.50 Due to its method of action, imiquimod has the potential to exacerbate pre-existing autoimmune disease. In the second open study discussed above, 38% of patients (six of 16) discontinued treatment early due to side-effects, but still had lesion clearance.50 Benefit has been reported in the treatment of SCC in situ in immunosuppressed patients, although many of these reports have been of imiquimod use in combination with another therapy, making interpretation of its role difficult.55-57 Combinations of therapies are discussed in section 11.10.1. Cryotherapy is a simple, inexpensive and quick method of treating SCC in situ, with the advantage of accessibility in the outpatient setting. Clearance rates for cryotherapy vary widely, probably reflecting differences in the techniques and regimens used, with failure rates in the order of 5–10% in the larger series, provided that adequate cryotherapy is used [e.g. liquid nitrogen cryotherapy, using a single freeze–thaw cycle (FTC) of 30 s, two FTCs of 20 s with a thaw period, or up to three single treatments of 20 s at intervals of several weeks].58-61 However, such doses do cause discomfort and may cause ulceration, especially on the lower leg. In the largest, prospective open study, a single 30-s FTC on between one and eight lesions, more than half of which were on the calf, achieved a clearance rate of 100% and recurrence rate of 0·8%, with follow-up periods ranging from 6 months to 5 years.59 In contrast, in a retrospective comparison study the use of a 20-s freeze on 91 lesions resulted in lower clearance rates of 68% after one treatment and 86% after retreatment of lesions, with partial response 12 weeks later.60 From the available studies it would appear that the more aggressive approach consisting of a freeze of 30 s at least once, or 20 s at least twice, yields better results, but the optimum freeze time, the number of freezes in one treatment cycle and the role of retreatment visits are not clear. Although lesions treated with cryotherapy healed better than those with radiotherapy,60 they did not heal as well as those treated with curettage or PDT. Cryosurgery may be useful in low-risk situations for patients who prefer to avoid surgery or cumbersome topical treatment, but one must balance the need of a cure against the potential adverse effects of aggressive FTCs. Cryotherapy was compared with MAL-PDT and 5-FU in a large European RCT, discussed in section 11.7. In an earlier RCT of ALA-PDT vs. cryotherapy, the latter produced 100% clearance in 20 patients following one to three treatments of liquid nitrogen using one FTC of 20 s on each occasion (50% success after a single treatment), but ulceration was observed following cryotherapy in 25% of lesions.61 A prospective, nonrandomized case-comparison study comparing curettage vs. cryotherapy found better healing, less discomfort, fewer complications and a lower recurrence rate with curettage.62 Cryotherapy appears to have a moderate success rate with prolonged freezing times (recurrences < 10% at 12 months), but complications such as poor healing and hypopigmented scarring are more likely to occur, particularly in poorly vascularized areas. PDT and curettage both have higher success rates and less discomfort overall, but are more time consuming and/or expensive to perform. Curettage and cautery has been advocated as one of the simplest, least expensive,63 safest and most effective methods of dealing with SCC in situ, but its success is determined by the skill of the operator.64 Studies using curettage and cautery give a wide range of cure rates, with larger series suggesting a recurrence rate of 20%, but they often lack details of treatment regimens and equipment used.3, 31 High cure rates can be achieved; one study showed a recurrence rate of 2% (one out of 52) over 4 years,65 while another study reported a recurrence rate of 10% (eight of 83) after a follow-up of 2 years.66 These smaller studies have shown recurrence rates similar or superior to excision. In a prospective but nonrandomized trial of curettage and cautery (44 lesions) compared with cryotherapy (36 lesions) involving 67 patients, curettage was preferable in terms of pain, healing and recurrence rate62; 74% of lesions were on the lower leg. Median time to healing with cryotherapy was 46 days (90 days on the lower leg), compared with 35 days (39 days on the lower leg) for curetted lesions, and reported pain was significantly greater with cryotherapy. Recurrences were more likely following cryotherapy (30%, 13/44) compared with curettage (11%, four of 36) during a median follow-up period of 2 years, although the cryotherapy regimen was less aggressive than that used by the authors in most studies of this technique. In another comparative retrospective study, clearance rates were 93% for curettage and cautery, 87% for 5-FU and 61% for cryotherapy,37 and the authors also observed that curettage and cautery required the fewest clinic visits for these treatment modalities. This is a simple, rapid and effective treatment for SCC in situ of limited size and located in suitable areas. It allows for verification of the diagnosis and confirmation of the intraepithelial nature of the lesion. Cosmetic outcome, body site, healing properties and vascularity of the area need to be considered. The largest retrospective study reported to date, of 155 patients, showed recurrence rates of 19·4% over an unspecified period.67 Two other studies reported lower recurrence rates of 2·8% (three of 109 lesions) over a mean follow-up period of 31 months,11 and 5% (three of 65 lesions) after a follow-up period of 1–5 years.31 While it is logical that excision should be an effective treatment, the evidence base is limited. Additionally, lower-leg excision wounds may be associated with considerable morbidity.37 Mohs micrographic surgery may be indicated for digital SCC in situ (around the nail in particular) and for some cases of genital (especially penile) SCC in situ for its tissue-sparing benefits. There may also be a role for Mohs in recurrent or incompletely excised lesions. A large national 10-year retrospective study of 270 patients has reported on micrographic surgery for tissue sparing at head and neck sites;12 this study included 128 cases of previously treated head and neck SCC in situ. Among the 270 cases analysed, 94 had had previous cryotherapy, 18 curettage and cautery, 44 excision (10 incomplete) and one radiotherapy (some had been treated with more than one modality); nearly all referrals cited poorly defined tumour, recurrent or incompletely excised tumour, or tumour site as the rationale for micrographic surgery, so it cannot be assumed to be routinely necessary or cost-effective. The overall 5-year recurrence rate for the 95 patients was 6·3% (3% for primary tumours and 9% for recurrent tumours). PDT for SCC in situ involves topical application of the photosensitizer prodrug ALA or its more lipophilic methyl ester MAL.68 MAL is applied under occlusion for 3 h followed by illumination using red light, with narrowband light-emitting diode (LED) sources in routine use. Treatment is repeated 7 days later and again after 3 months, if required. Several protocols have been described for ALA-PDT in SCC in situ as outlined below, with nonformulary ALA often used. Fluorescence diagnosis, the identification of lesions using the fluorescence detectable after MAL/ALA occlusion, achieved 100% sensitivity (higher than clinical evaluation alone) and a specificity of 85·7% in a recent study in SCC in situ.69 The opportunities for lesion delineation and detection of recurrences using fluorescence, and more detail on treatment protocols and light sources used in PDT are reviewed in the BAD British Photodermatology Group guidelines on PDT.68 Complete clinical clearance rates of 88–100% are reported 3 months after one cycle of MAL-PDT, with 68–89% of treated lesions remaining clear over follow-up periods of 17–50 months.40, 70-73 A multicentre, randomized study compared MAL-PDT with cryotherapy or 5-FU in 225 patients with 275 SCCs in situ.40 MAL was applied for 3 h then the sites were illuminated with broadband red light, with treatment repeated after 7 days (16% of lesions required retreatment after 3 months). The lesion complete response rates 3 months after the last treatment were similar with all regimens (93% for MAL-PDT, 86% for cryotherapy, 83% for 5-FU). PDT gave superior cosmetic results compared with cryotherapy or 5-FU. Clearance rates for all three therapies were similar after 2 years, with 68% of lesions cleared following PDT, 60% after cryotherapy and 59% after 5-FU.70 A similar 3-month efficacy rate of 88% was observed in an open study of MAL-PDT (only one cycle of two treatments, 7 days apart), for 41 SCCs in situ, using a narrowband red LED source, with sustained clearance of 71% at 24 months.71 Further open studies of 51 and 43 lesions treated by the same MAL-PDT protocol observed 76% and 89% sustained clearance after 17 and 50 months, respectively.72, 73 Efficacy rates for ALA-PDT of 80–100% reported in previous guidelines remain valid, with a 90% clearance of 19 lesions in an open study in patients unsuitable or unwilling to have surgery, with 77% still clear at 2 years, but only 53% at 5 years following only one session of ALA-PDT with a nonformulary ALA, and with two penetration enhancers added.4, 74 PDT may be particularly appropriate for large lesions (> 3 cm diameter), with two treatments of MAL-PDT, 1 week apart, clearing 96% (22/23) of lesions at 3 months, with sustained clearance after three recurrences of 83% at 1 year.75 Body site does not appear to impact the efficacy of PDT, with protoporphyrin IX accumulation identical in SCC in situ located on acral and nonacral sites.76 Digital SCC in situ was treated with ALA-PDT in four patients, with good cosmetic and functional results (one recurrence at 8 months responded to retreatment).77 Case reports identify successful treatment of SCC in situ on the nipple, subungual, in poor healing sites on the lower legs, and in the setting of epidermolysis bullosa and radiation dermatitis.38, 78-82 In a trial comparing ALA-PDT for actinic keratoses or SCC in situ in OTR compared with immunocompetent controls, despite comparable cure rates of 86% at 4 weeks, significantly more recurrences occurred in the OTR group over 48 weeks.83 A comparison of MAL-PDT with topical 5-FU in only five OTRs with SCC in situ is discussed in section 11.2.42 PDT is normally delivered in a hospital setting, but novel light sources that can be worn by patients have also been used to treat SCC in situ, although published numbers are small.84, 85 A recent open study of ambulatory PDT in NMSC included 30 patients with SCC in situ, with an overall 84% lesion response reported at 1 year (including 10 SCCs in situ with follow-up).86 Red narrowband LED light is used most often; however, a square wave intense pulsed light, with reduced dose variability, cleared all nine SCCs in situ in one case series, with all lesions remaining clear after a follow-up period of 4 months.87 Pain is a common side-effect, but PDT for SCC in situ has been observed as less painful compared with PDT for actinic keratoses.88 In a large series reporting the prevalence of severe pain during a standardized ALA-PDT, 21% of 1015 treated SCCs in situ were associated with severe pain, similar to 20% for superficial BCC (sBCC), with a direct association between lesion size and pain.89 A comparison of pain with ALA-PDT or MAL-PDT, in 20 SCCs in situ and 20 sBCCs, failed to show any difference between the photosensitizing agents.90 In a national survey of usage of topical PDT across 12 sites in Scotland, 104/382 lesions included were SCC in situ. Severe PDT-induced pain occurred overall in 10% of treatments, moderate pain in 18% and mild to no pain in 72%.91 Detailed assessment of adverse events associated with PDT is discussed elsewhere, but PDT appears a safe and generally well-tolerated therapy.68 Although one patient with clinically diagnosed SCC in situ treated with PDT was diagnosed with melanoma at the same site a few months following treatment, it is uncertain whether the treatment contributed, given the lack of initial histology.92 Various radiotherapy techniques have been used to treat SCC in situ, with no standardized protocol, and a recent literature review concluded that both high- and low-dose regimens appear equally efficacious.93 Disadvantages include cost, patient inconvenience and poor healing, particularly on the leg. Advantages are that it can be used to treat areas where surgical modalities are difficult, and it can be used even on the scalp.94 Complete clearance of lesions is widely reported following radiotherapy, but impaired healing on the lower leg was observed in a large retrospective study, leaving the authors to recommend that radiotherapy should not be used on lower-leg lesions.60 Cox and Dyson60 reviewed the use of external beam radiotherapy (26 total dose combinations) in 59 SCC in situ lesions, with poor healing or failure to heal in 33%, which was related to patient age, diameter of field and the dose and energy of radiotherapy used, with no apparent effect of fractionation on healing.