CHAPTER 24
Principles of Radiotherapy

Charles G. Kelly and John Frew

Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK

Introduction

The clinical effects of ionizing radiation on the skin have been known since the discovery of X-rays in 1895 [1, 2]. Initially both benign and malignant skin conditions were irradiated and dose and clinical indications were chosen empirically with little knowledge of the late effects of radiation on skin and subcutaneous tissue. Indications for treating benign disease by irradiation have declined since the advent of topical steroids.It is in the best interest of patients with skin tumours to be seen in a clinic where the expertise of specialists in radiotherapy and oncology, plastic surgery and micrographic surgery as well as dermatology are present, and this is being achieved with the mandatory development of multidisciplinary team meetings and clinics in the UK as described in improving outcomes guidance [3].

Ionizing radiation in the treatment of skin cancer

X-ray photon beams: megavoltage and kilovoltage X-ray therapy

X-rays are part of the electromagnetic spectrum, of shorter wavelength and more energetic than UV light. The most commonly used form of therapeutic radiation is megavoltage radiotherapy using energies of greater than 1 million electron volts (>1 MeV), delivered by linear accelerators in the treatment of deep-seated tumours. Previously, these beams have usually not been suitable for the treatment of skin cancers because of their greater penetration and skin sparing properties, but that has changed in the last few years, with advances in beam delivery technology, although megavoltage beams are still only used for a small minority of skin cancer patients and in particular clinical situations. X-rays in the kilovoltage range (50–140 kV) are very suitable for treating skin cancer as their maximum energy is deposited on the surface. Fall off subsequently is exponential (Figure 24.1), and some radiation dose does reach underlying subcutaneous structures. Higher kilovoltage beams can be used for thicker tumours.

Image described by surrounding text. — **Figure 24.1** Approximate per cent depth dose values for 90 kV superficial X-ray beam.

Electron beams

Beta rays are electrons and can be derived from radioactive isotopes, such as ^strontium-90 or be produced by a linear accelerator. An electron beam differs from a superficial X-ray beam or other photon beams, as the energy does not fall off exponentially as the beam goes through tissue but builds up to a peak and then falls off rapidly (Figure 24.2). The depth of penetration is proportional to the energy of the beam. A useful treatment depth in centimetres is approximately one third of the energy of the beam, so a 4.5 MeV electron beam will be useful for treating to a depth of 1.5 cm, and a 12 MeV beam to 4 cm. The width at the peak of the beam also increases with electron energy giving more of the plateau at the peak at higher energies, as shown by the representation of the 9 MeV beam shape in Figure 24.2. This can be useful when trying to enclose all of a thick tumour within the highest energy part of the beam. To avoid skin sparing, tissue equivalent material such as wax or paraffin gauze is applied over the tumour so that energy is deposited in this ‘build-up’ material, moving the beam peak left towards the skin surface in Figure 24.2.

Superficial X-ray therapy is indicated for the majority of skin cancer treatments. However, there is a slightly higher risk of late bone and cartilage necrosis with this modality, as X-rays are absorbed proportionally more in high-molecular-weight tissues than in soft tissue. Electrons are absorbed similarly in all tissues, and have the advantage of sparing sensitive underlying tissues. These may be the modality of choice for tumours on the pinna, scalp, dorsum of the hand and tibia. Superficial X-rays have been used successfully in the past in these sites [1], but electrons are now preferred [2].

Unfortunately in practice, electrons have a limited use in the treatment of common skin cancers. As an electron beam is produced by a linear accelerator, which is much larger than a superficial X-ray machine, the treatment applicator is unwieldy and the minimum applicator size on the skin is 4 cm² for a reliable dose calculation. Air cavities can give unacceptable dose inhomogeneity with electrons and eye shielding is not possible for treatment of periorbital tumours. Setting up treatment fields with electrons is often more time-consuming than with superficial X-ray therapy.

It is possible to irradiate the whole skin area with an electron beam [3, 4, 5, 6, 7, 8]. The minimal depth dose characteristics that may be achieved avoid the irradiation of subcutaneous structures, which would occur if X-ray therapy that is absorbed exponentially was used. This technique is used in the treatment of mycosis fungoides [4]. Multiple radiation fields are combined to give a homogeneous dose to the whole skin down to a depth of approximately 1 cm.

Moulds, applicators and implants

Other treatment modalities available for the irradiation of skin cancer, but in less common use, are using a ‘mould’, which is a cast loaded with radioactive material applied to the surface of the tumour and secured in place for the required treatment time, or using interstitial brachytherapy as described below for the treatment of keloids [1, 2]. The use of these techniques has seen a slight renaissance in some countries in the last decade with the introduction of more modern applicators [3]. Cosmetic results are good but there is a need for hospital admission for radiation protection reasons and results depend on local expertise.

Superficial radiotherapy treatment technique

The superficial X-ray tube is manoeuvrable, and the patient can be made comfortable on a treatment couch with an applicator resting on the skin to be treated (Figure 24.3). The tumour and a margin of normal tissue are treated with a standard applicator. If the tumour is an irregular shape in two dimensions, a piece of lead shielding 1.5 mm thick can be ‘cut out’ in the shape of the skin to be treated, and the applicator rests on this (Figure 24.4). The individual surface area for treatment is measured and the treatment time adjusted by calculation, giving the number of machine units which have to be delivered for each treatment.

Image described by caption. — **Figure 24.3** Superficial X-ray machine.

Once the applicator is in position, the radiographer leaves the treatment room. Treatments last for a few minutes on each occasion, and the patient is watched throughout using a remote camera system or special glass window.

Megavoltage X-ray therapy technique

While kilovoltage beams remain the most common modality to treat skin tumours, developments in radiotherapy technology over the last decade have increased interest in the use of megavoltage X-ray therapy in treating superficial skin lesions. The development of intensity modulated radiotherapy (IMRT) has enabled techniques where energy from megavoltage beams can be delivered separately and distinctly into individual small tissue volumes, building up complex 3D photon distributions with different doses delivered to specific areas adjacent to each other and with no or very little dose been given to areas containing organs at risk (OAR).

These advances in technology have allowed developments such as a ‘bathing cap’ distribution as seen in Figure 24.5, which allows homogeneous dose distribution across the skin of the scalp with rapid dose fall-off below the surface tissues resulting in much less dose being delivered to underlying brain.

An example of how this can be achieved is with a TomoTherapy^® linear accelerator, where the machine head revolves around the patient in a spiral movement with the beam being delivered by the machine head divided up into multiple tiny beamlets, which can all be adjusted individually to give dynamically a different dose to each small defined volume, allowing widely varying dose distributions to be built up in a 3D pattern within the patient.

These new megavoltage IMRT techniques are also useful whenever a relatively high homogeneous surface dose is required with sparing of underlying or neighbouring structures.

A further example of a ‘stocking’ distribution is shown in Figure 24.6a,b where an appropriate dose could be delivered homogeneously to the foot and ankle of a patient with skin lymphoma, sparing underlying tissues. The benefit of using this method of treatment can be seen in Figure 24.6c,d before and after treatment. The foot and lower leg were held in position for treatment using the immobilization device in Figure 24.6e.

Radiosensitivity

All radiation is destructive. The basis of radiotherapy is that abnormal cells are more radio-responsive than differentiated cells. Radio-responsiveness and radio-curability are dissimilar and are functions of differences in cell population kinetics, so a rapidly resolving cancer may recur and a slowly resolving tumour may be completely cured. Radiotherapy is usually given as a fractionated course, as the intervals between doses allow for the recovery of normal cells. The effect of a dose of radiation is reduced by increasing the number of fractions in which it is given or by lengthening the total overall treatment time. The effect of irradiation can be modified by anoxia, infection, oedema, trauma and any inborn genetic susceptibility. The face tolerates irradiation well and radical dosages may be accompanied by good cosmetic results [1].

When irradiating benign conditions, the minimum dose and the lowest voltage appropriate to achieve the desired effect should be chosen. The threat of radiation carcinogenesis must clearly be seen in the context of the clinical indication for treatment. There is a threshold for somatic radiation changes which need not be breached in the treatment of benign conditions. The late radiation sequelae of treatment given many years ago are inexcusable with modern standards of dosimetry and equipment, and should not be seen in the treatment of benign diseases [2, 3].

Indications for radiotherapy

Benign disease

Some of the misconceptions about the role of radiotherapy have arisen because of its widespread use in the past for the treatment of benign conditions. X-ray production was discovered in 1895, and soon afterwards it was noted that the antiproliferative effect of low-energy X-rays was advantageous in the short term in a variety of visible tumours and benign dermatoses, and sometimes multiple re-treatments were offered. There was, however, no dose measurement apart from the biological effect of ‘skin erythema’, no radiation protection for workers or patients, and no appreciation of the late effects of radiodermatitis, leukaemia and other malignancies, and of skin cancer induction after a very long latent period.

Radiation epilation for tinea capitis, a treatment offered widely in Europe, well demonstrates radiation carcinogenesis. In Israel, between 1946 and 1960 over 20 000 immigrant children were treated with radiation soon after their arrival, by government order, with twice the subsequent incidence of cancer, usually of the brain, head and neck [1]. Skin cancers induced by this treatment have a very long latent period, often over 30 years, and cases treated in the 1930s and 1940s have been seen until recently in cancer treatment centres in the UK (Figure 24.7). For a fascinating and well-illustrated discussion of these early treatments and their consequences see Mould [2].

Radiotherapy is used much less now in the management of benign skin conditions than formerly and then usually only after other treatment modalities have failed or are contraindicated. In some conditions, such as psoriasis and eczema, there is a response to radiotherapy but often the benefit is only temporary [3, 4, 5, 6, 7]. This coupled with the risk of late radiation-induced malignancy has led to the decline in its use in all but the most refractory of cases. It is also still used occasionally in the management of keratoacanthoma where the differentiation from squamous cell carcinoma (SCC) cannot be made with complete confidence [8, 9]. Other rare uses are in Darier disease [7], familial benign chronic pemphigus [7] and acropustulosis of Hallopeau.

Recent National Institute for Health and Care Excellence (NICE) guidance on the use of Grenz rays, which are very low kilovolt X-rays absorbed chiefly in the epidermis, advises that the evidence for their safety and efficiency is very limited, and that their use in inflammatory skin conditions be limited to carefully selected patients who are refractory to other treatments, and preferably under trial conditions or at least with national data collections [3, 7, 10].

Keloids (see Chapter 96)

These represent the most common benign condition now treated with radiotherapy. Intractable keloids resistant to intralesional steroids or other conventional treatment may respond well to radiation. Excision of the keloid with early irradiation of the scar and stitch marks is more successful, but in some sites, for example the tip of the shoulder or upper middle chest where surgery is inadvisable, good response of pain, itch and redness can be achieved with some regression of the keloid itself. Relatively high doses are necessary; these will cause temporary pigmentation, which will remain for many months in pigmented skin. Doornbos et al. [1] noted that 17 of 18 unexcised keloids that were less than a year old regressed with 1500 cGy given in three treatments over 6 days at 120 kV. Older keloids respond less well to irradiation. The most satisfactory management of keloids is post-excision irradiation where a dose–response relationship can be seen. Total doses less than 900 cGy, irrespective of fractionation and postsurgical interval, did not prevent recurrence. Three doses of 400cGy were given by Kovalic and Perez [2] with a 73% success rate. Using the commonly employed dose of 900 cGy, Lo et al. [3] described an 85% success rate and Borok et al. [4] a 96% response rate. No late sequelae or carcinogenesis was described by any of the previously quoted authors with follow-up in excess of 30 years.

As well as using superficial X-rays or electron beam radiotherapy [5], treatment can be given using a radioactive iridium wire implant. With the latter technique, at the time of excision a small plastic tube is inserted below the incision with both ends of the tube exposed. The patient is then transferred to the radiotherapy department within 24 h and the tube is loaded with iridium wire and the scar irradiated to a dose of 20 Gy at 2 mm from the wire over 2 days [6]. Escarmant et al. [7] describes the results of treating 783 keloid scars in 544 patients with interstitial iridium implants. Skin applicators using either high-dose rate or low-dose rate brachytherapy have also been used [8].

Malignant skin disease

Basal cell carcinoma and squamous cell carcinoma of the skin (see Chapters 141 and 142)

For most small basal cell carcinomas (BCC) or SCC without nodal involvement, surgical excision or radiotherapy will give excellent cure rates [1, 2, 3, 4, 5].

Superficial radiotherapy has a long history in the successful treatment of BCC and SCC skin. 1695 such patients received treatment in 1945 at the Queensland Radium Institute [6]. A number of mature series have been reported, dated from 1947 onwards [7], and shown cure rates of 90% or over.

Treatment of choice

If cure is the intention, then surgery or radiotherapy are the treatment options, although a variety of other modalities including cryotherapy, curettage, photodynamic therapy and topical therapies (e.g. imiquimod) may be appropriate for certain tumours [8, 9, 10].

The decision as to which is the most appropriate modality will depend on several factors. These include the size and location of the tumour, any involvement of underlying tissues and the likely functional and cosmetic outcome. The majority of low-risk BCCs can be managed satisfactorily by simple surgical techniques with good cosmesis and low recurrence rates. For larger BCCs and SCCs in critical sites, particularly around the eyes, ears and nose, Mohs micrographic surgery followed by appropriate surgical reconstruction is now widely used (see Chapter 20). Radiotherapy should, however, still be considered as a valuable treatment option, and in some clinical situations as useful as surgery [11]. The patient's overall performance status and co-morbidities are as important as the complexity of any intervention under consideration. In reaching a decision, social factors such as accessibility of treatment centres, ability to cooperate with treatment and patient preference all need to be taken into account. The regular skin cancer multidisciplinary team meetings held throughout the UK are very helpful in guiding such decisions. Cure is not always a realistic proposition and radiotherapy can offer very worthwhile palliation (Figures 24.8 and 24.9).

Radiotherapy has a role to play in the treatment of almost all malignant skin conditions but, because there is considerable regional and national variation in access to radiotherapy and awareness of its value, its current use is patchy [8]. Although radiation damage with skin atrophy, telangiectasia, necrosis and ulceration occurred in the past, better dosimetery, a wider range of radiotherapy modalities [12] and more careful fractionation have considerably reduced this risk. In the UK, multidisciplinary skin cancer teams are now helping to ensure that the most appropriate modality is offered to every patient with skin cancer. This is in contrast to previous practice where only 2% of patients with BCC were referred to joint clinics [13] or a radiotherapeutic option was needlessly dismissed [14]. UK National Guidance [15] recommends that all health professionals treating skin cancer should be members of such a team and should work to locally approved protocols based upon nationally accepted guidelines, such as those of the British Association of Dermatologists [16]. A similar approach has been recommended in American guidelines [17].

Surgery or radiotherapy

It is not disputed that surgery offers a better cosmetic result with the passage of time, nor that radiotherapy is able to preserve existing structure and function, although not of course able to replace tissue destroyed by tumour.

Few trials have compared surgery directly with radiotherapy. Avril et al. [18] showed that in 347 patients with facial tumours less than 4 cm in diameter, a surgical recurrence rate within 3–5 years was 1/174 in the surgery group compared to 11/173 for radiotherapy. The cosmetic result was better with surgery. However, the radiotherapy regimens were heterogeneous, and the surgical results exceptionally good, better even than for Mohs microsurgery, where one large series had a 30-month recurrence of 3/160 tumours, compared to 5/171 for conventional surgery [19]. Published studies of radiotherapy for skin cancer are, however, remarkably consistent in reporting high long-term control rates of well over 90% [20, 21]. Advantages and disadvantages of each modality are summarized in Table 24.1.

Table 24.1 Patient factors influencing choice of skin cancer treatment.

Surgery generally preferred	Radiotherapy may be preferred
Younger patients	Older patients
Multiple tumours	If surgery would result in poor cosmetic result or loss of function, particularly if micrographic surgery not available (e.g. nasal tip, lips, periocular, ears)
Gorlin syndrome [22]
Infiltrative basal cell carcinomas
Bulky tumours >6 cm	To avoid complex surgical reconstruction in the frail elderly
If there is erosion of bone or cartilage
Tumours located on the trunk	To avoid general anaesthesia in patients who would not tolerate surgery under local anaesthesia
Ano-genital tumours
Tumours below the knee [23]	To avoid general anaesthesia in patients who would otherwise require this for surgical management

There is little difference in outcome between external beam radiotherapy using superficial X-rays or an electron beam [24, 25]. Locally placed moulds or applicators have also been used for malignant skin tumours, placing a radioactive source over the tumour and leaving this in position for a predetermined period [12, 13], or implanting radioactive wire into the tumour-bearing tissue. As described earlier, megavoltage radiotherapy using IMRT is now starting to be used for treating larger skin areas, often when surgery would not be possible, such as treating large areas of the scalp or peripheral limbs.

The areas which have traditionally been considered as not suitable for radiotherapy, such as over the nose, pinna, dorsum of the hand or anterior lower leg can be treated if careful consideration is given to the volume treated, the total dose and the fractionation. It is also important to consider the general fitness of the patient and the condition and physiological reserve of the skin in the site to be treated [26, 27, 28, 29].

There are some patients who, for practical reasons, cannot have radiotherapy. If patients are confused or unable to lie still because of confusion or neurological disease, then it can be impossible to deliver radiotherapy effectively and safely.

Adjuvant and salvage radiotherapy for skin cancer

Although ideally the patient should receive a single curative modality of treatment, sometimes patients are presented who have had a macroscopic excision of an SCC or a BCC but involved margins histopathologically.

Adjuvant radiotherapy has been advocated by some authors [30, 31, 32] where there has been inadequate excision and further surgery is either not possible or not recommended; if the tumour shows prognostic indicators of poor outcome such as positive lymph nodes, especially with extracapsular spread; with a large primary SCC; or in higher risk primary tumours of the head and neck. Adjuvant radiotherapy may improve outcome in SCC, especially if there is perineural invasion, when there is an increased risk of incomplete clearance even after Mohs surgery [31]; there is also some evidence that delaying radiotherapy may result in early tumour recurrence [33].

Because of the risk of nodal spread or perineural invasion from an incompletely excised SCC, it is sensible to offer ‘postoperative’ radiotherapy to the scar and tumour bed using a full normal dose and fractionation regimen. With a well-healed scar or skin graft, the radiation reaction is often very mild.

The situation is different for BCC, where Lui et al. [34] reported a series of 186 incompletely excised BCCs: 119 had immediate radiotherapy postoperatively, and 67 ‘wait and see’ with radiotherapy for clinical recurrence. The predicted cure rates at 5 years were 91% versus 61%, respectively, but 10-year cure rates of 90–92% were observed for both immediate and delayed treatment. When surgical re-excision is inappropriate, it may thus be reasonable, particulary in the elderly, merely to observe and to offer adjuvant radiotherapy only for clinical recurrence.

Radiotherapy dose fractionation and treatment regimens

Radiotherapy regimens have evolved empirically over a long period of time and a wide range is in current use. Generally, the greater the fractionation of the total dose, i.e. the smaller the individual dose administered at each session, the better the cosmetic outcome. This is obviously very important to some patients, but others are content to accept a poorer cosmetic outcome in exchange for fewer hospital visits (Table 24.2).

Table 24.2 Commonly used superficial radiotherapy dosage regimens for basal cell carcinomas and cutaneous squamous cell carcinomas. These fractionation regimens are only examples. Many centres will have other similar but locally derived dose fraction regimens.

Total dose (Gy)	No. of fractions	Fractionation interval
18	1	–
28	2	7 weeks apart
35	5	Daily (for tumours less than 4 cm in diameter)
45	10	Daily (for tumours more than 4 cm in diameter)

The SI unit of absorbed dose is called the Gray (Gy), and is 1 Joule/kg. This unit has replaced the rad. Note that 100 rad = 1 J/kg = 1 Gy; 1 rad = 1 cGy (centigray). The dose prescription is defined by the total dose given, the energy of the beam, the number of fractions given, the total number of days over which treatment is given and the volume or area treated. For example, a typical prescription for the treatment of a small BCC might be ‘35 Gy using 90 kV superficial X-ray beam given in five fractions over 5 days to a 3 cm diameter circular area’. This time–dose relationship is crucial to understanding the biological effect.

Dose and fractionation regimens are similar for BCC and SCC. There is a small therapeutic ratio between tumour cure and normal tissue necrosis, and even a slight alteration of dose or fractionation can be critical; in a retrospective study of 1005 BCCs and SCCs treated by superficial X-rays in 1976 at the Christie Hospital, Manchester, Chan et al. found that for a field size of 3 cm² or less, a single fraction of 20 Gy gave a 10-year disease-free rate of over 90%, with late necrosis rate of 6%. An increase of dose to 22.5 Gy did not improve tumour control rates, but did significantly increase late necrosis [35].

Fractionated radiotherapy is usually preferred for larger tumours, as cure rates are higher and better long-term cosmetic results are achieved [36, 37, 38].

Radiotherapy for particular skin sites: basal cell and squamous cell carcinoma

Eyelid (Figure 24.10)

The upper eyelid, a rare site for skin cancer, is best treated surgically, as keratinization of the tarsal conjunctiva may cause subsequent traumatic damage to the cornea. Tumours of the lower eyelid, however, are often suitable for treatment with superficial X-rays. A protective metal internal eyeshield is placed like a large contact lens over the globe of the eye after the application of local anaesthetic eye drops, with an applicator resting on this and on the lower lid tumour with an appropriate margin. The whole lower eyelid can be successfully treated in this manner if required.

Inner canthus (Figure 24.11)

These tumours, close to the orbit, have a high cure rate if there is meticulous attention to dose calculation. An individual thin lead mask is made for the patient by mould technicians, with the treatment area cut out. This provides a seating for the applicator, avoids the possibility of trauma on the treated side and protects the contralateral eye from the exit beam. If the naso-lacrimal duct has been damaged by tumour and the patient has epiphora for this reason, then radiotherapy is not likely to reverse this symptom. However, it is uncommon for radiation per se to cause a new stenosis of the ductal system. Different authors advocate either radiotherapy or Mohs micrographic surgery depending on the size of the tumour, potential for disfigurement or loss of function [1, 2].

Ear (Figures 24.12 and 24.13)

Because tumours of the pinna and outer ear canal have close proximity to cartilage, electrons are preferred for treatment (see earlier). In a study of 62 patients treated by orthovoltage techniques, however, local control was achieved in 97% of cases and only one of the six cases with clinically suspected cartilage necrosis failed to heal spontaneously [3]. In a large Canadian study, in which 93% of patients remained tumour free at 10 years [4], persistent ulceration was observed in only 3%, and did not relate to beam energy but to dose and fractionation. However, electron treatment does give very good results for tumours covered by a 4 or 5 cm diameter applicator [5] and most departments will offer electrons unless for particular reasons the patient is unable to tolerate the Linac procedures. The visible tumour is delineated, with a margin of at least 1 cm to account for the depth dose characteristics of the electron beam, and the fact that the smallest reliable treatment applicator size is 4 cm diameter. The patient lies on the treatment couch with the ear for treatment uppermost, and wax or paraffin gauze is applied to make a level treatment surface, to fill in air gaps of sufficient thickness to avoid skin sparing. If the tumour is on the posterior surface of the pinna, the ear itself can act as a build-up zone, with wax as a posterior filler to ensure an even dose. A lead shield behind this protects the scalp. Once this ‘sandwich’ is in place, the applicator is brought down firmly to rest on the surface, and treatment delivered using 5 or 6 MeV electrons.

Nose

Although skin cancers here are very closely applied to cartilage, in practice superficial X-rays give excellent control rates, and often a better cosmetic result than tumours irradiated at other sites. A lead plug is inserted inside the nostril to protect nasal mucosa from the exit beam. At the naso-labial fold, the depth to be treated needs careful consideration.

Other areas of the face (Figure 24.14)

Even large BCCs can do well with radiotherapy [6].

Lip (Figure 24.15)

Squamous carcinoma of the lip has a high local cure rate with radiotherapy using either electrons or kilovoltage X-rays [7]. Treatment margins should be generous, because of the tendency for the tumours to spread mucosally, usually at least 1 cm of apparently normal tissue. The whole thickness of the lip is treated, choosing appropriate electron energy and build-up wax, or higher energy kilovoltage X-rays (300 kV). A wax-coated lead gum shield protects the inner mouth from the exit beam, but a patch of mucositis within the mouth is inevitable, and will interfere with normal eating and drinking for a few days after treatment.

The patient is usually able to tolerate treatment to most of the upper or lower lip at one time, but not both areas simultaneously. The final cosmetic result is usually excellent.

As well as electron treatment, local brachytherapy can also be used for lip carcinoma [8].

Parotid and cervical lymph node involvement from cutaneous squamous cell carcinoma

A subset of patients who develop cutaneous SCC of the skin of the head and neck risk developing regional disease within parotid or cervical nodes, with worse outcomes [9]. Several studies have now shown that combination treatment with surgery and adjuvant radiotherapy gives higher rates of local control of parotid and cervical node metastasis than either treatment given alone [9, 10, 11, 12, 13].

Radiotherapy for particular skin tumours

Basal cell carcinoma (see Chapter 141)

Radiotherapy is useful for the primary treatment of small basal cell carcinomas or larger lesions where surgery will leave a poor functional or cosmetic result (see earlier) [1, 2, 3]. It should not be used for re-treating BCCs which have recurred after previous radiotherapy as they may then behave in a more aggressive manner [4]. The infiltrating (morphoeic) BCC subtype or the presence of underlying bone or cartilage involvement are relative contraindications to radiation treatment [5].

Squamous cell carcinoma of the skin (see Chapter 142)

As with BCC, radiotherapy can be used as either the primary modality of treatment or as adjuvant treatment after surgery if there is a narrow surgical margin of clearance, the margin often being determined by the particular anatomical site of the tumour. The technique and dose is the same as that for treating a basal cell cancer, but a wider margin is taken around the tumour and the patient is subjected to a more frequent and longer follow-up, as suggested in the British Association of Dermatologists guidelines [6]. If the SCC has developed on the face, it is mandatory to check for cervical lymphadenopathy. Radiotherapy may be especially useful for SCC on or around the nose where resection may be incomplete or the potential for reconstruction suboptimal [7].

The size of the SCC is also important with one study showing radiotherapy giving local control in over 90% of SCCs less than 1 cm, but in only 56% of tumours larger than 5 cm [8].

Adjuvant radiotherapy may reduce the development of nodal disease in higher risk cutaneous SCC as described by Veness [9].

Radiotherapy can also be useful in palliation of advanced skin tumours and in some patients give long-term survival [10].

Bowen disease (see Chapter 142)

Radiotherapy can be an effective treatment for Bowen disease [3], but it is not commonly used, particularly since the introduction of photodynamic therapy (see Chapter 22). Lesions on the leg have to be treated with caution [11, 12] as there is a danger of ulceration and very slow healing if large areas are treated. A recent retrospective review of 44 cases by VanderSpek et al. where radiotherapy was used as a primary treatment or for managing residual disease showed a crude local control rate of 93% [13].

Melanoma (see Chapter 143)

Melanoma cells are not insensitive to radiotherapy as is sometimes stated (Figure 24.16), but they do require higher dose per fraction regimens to overcome their higher radio-resistance. Patients may thus be given larger individual doses in less frequent fractions (‘hypofractionation’) [14]. The main indication for the use of radiotherapy in melanoma is for palliation of cutaneous and visceral metastases [15]. There have been uncontrolled studies suggesting that adjuvant radiotherapy may improve local control [16, 17], and recently the Trans Tasman Radiation Oncology Group (TROG) reported that patients at risk of regional failure (as defined by having multiple nodes, large nodes or extracapsular spread) randomized to receive adjuvant radiotherapy had a decreased risk of such failure at a median follow-up of 6 years compared with those who were not; there was, however, a high (40%) incidence of severe lymphoedema in those receiving treatment of the groin and no relapse-free or overall survival benefit [18, 19, 20]. The impact of adjuvant radiotherapy on survival is unknown but may be minimal even if local control is improved [21].

Lentigo maligna and lentigo maligna melanoma (see Chapter 143)

Radiotherapy has been used successfully in both of these conditions. In one German study, there was no recurrence in any of 42 patients with lentigo maligna, with a mean follow-up of 15 months, and only two of 22 patients with lentigo maligna melanoma showed local recurrence. Cosmetic results were also reported as good or excellent in the majority of patients [22]. Similar complete responses with good cosmetic outcomes have been reported from Australia [23] and Canada [24].

Merkel cell carcinoma (see Chapter 145)

These tumours of neuroendocrine origin are most common on the head and neck, but can occur elsewhere on the skin. They have a tendency to recur locally after conventional surgical removal and improved local control has now been shown in a large number of studies with a combination of wide excision and adjuvant postoperative radiotherapy to the primary tumour site and local nodal drainage [25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35]; some studies have also shown improved survival [29]. Mohs surgery is now widely used for removal of Merkel cell carcinoma and, if complete excision is achieved, adjuvant radiotherapy may not add benefit in terms of improved local control or survival [36]. These are radio-sensitive tumours and radiotherapy has been used as a primary treatment, with local control rates of over 75% [37, 38, 39, 40, 41].

Kaposi sarcoma (see Chapter 137)

It is well known that these tumours are sensitive to low-dose radiotherapy. Either superficial X-rays or electron beams can be used depending on the thickness of the lesion(s) and consequently the depth of treatment required. Treatment is used cautiously as patients are prone to develop severe local reactions and mucositis. Radiotherapy is also used to palliate systemic disease such as pulmonary masses [42, 43].

Dermatofibrosarcoma protuberans (see Chapter 137)

This low-grade sarcoma has a propensity to recur after surgery alone and local control is improved by giving adjuvant radiotherapy [44, 45].

Carcinoma metastatic to the skin from other primaries

Radiotherapy can provide useful palliation for cutaneous metastases from visceral tumours such as breast, colon and lung (Chapter 147).

Squamous cell and basal cell carcinoma in transplant patients (see Chapter 146)

Skin tumours developing after organ transplant are known to have more aggressive characteristics and carry a poorer prognosis [46]. These patients develop more SCCs than BCCs, reversing the normal ratio, and often develop multiple skin cancers at an earlier age. There is no contraindication to using radiotherapy if surgery is considered inappropriate and it may be used as adjuvant therapy for patients with more aggressive tumours [47].

Cutaneous lymphoma

Radiotherapy represents the single most effective treatment strategy for cutaneous lymphomas. In contrast to other skin cancers, lymphomas are extremely sensitive to radiotherapy with doses as low as 4 Gy sometimes sufficient for local control. Surgery is therefore rarely indicated unless there is a solitary nodule where excision biopsy can be both diagnostic and provide definitive local treatment. The low radiotherapy doses are almost always within the constraints of normal tissue tolerance and therefore radiotherapy can be safely delivered with minimal risk of long-term complications.

An overview of the classification and management of lymphomas is described in Chapter 139. The following summarizes the technical aspects of radiotherapy with a focus on mycosis fungoides, which accounts for 50% of cutaneous lymphomas.

Mycosis fungoides (see Chapter 139)

Mycosis fungoides evolves slowly with the majority of patients falling into a favourable prognostic group with a median survival of more than 35 years from presentation [1]. It is essential to involve specialist histopathologists, dermatologists, oncologists and haematologists in a multidisciplinary approach to management.

Individual patches, plaques and tumours

Whilst mycosis fungoides is normally not isolated to one area, local radiotherapy is frequently utilized for troublesome lesions with a local control rate in excess of 90% [2]. The recurrence rates are dependent on the dose given with a dose–response relationship observed up to doses of 30–40 Gy [3]. In practice, lower doses are preferred, as they still convey a high chance of local control, are more convenient for patients and permit overlap of adjacent fields or re-treatment if necessary [4]. The current recommended UK doses are 8 Gy in two fractions for patches and plaques, and 12 Gy in three fractions for tumours [5].

Radiotherapy can be delivered with X-rays (low-energy superficial or orthovoltage), or electrons as described earlier with a directly applied field. The target volume is the clinically defined lesion with a margin of 0.5–1 cm laterally. Patches and plaques are typically treated to a depth of 7–9 mm with careful assessment of the thickness of tumours to determine the appropriate beam energy and thickness of bolus when using electrons [6].

More extensive tumours, particularly when extending around curved areas require careful radiotherapy planning. Patient-specific immobilization devices such as thermoplastic shells for the head and neck region are essential to ensure accurate delivery of the planned radiotherapy treatment. More complex techniques include matched field electron plans and IMRT plans using modern machines such as a TomoTherapy unit (see Figures 24.5 and 24.6). When delivering radiotherapy to large tumours, treatment is normally fractionated with typical doses between 20 and 24 Gy in 10–12 fractions [6].

Total skin electron beam therapy

A significant number of patients with mycosis fungoides develop generalized skin involvement. Total skin electron beam therapy (TSEBT) can provide excellent palliation particularly when other skin-directed therapies including psoralens and ultraviolet A (PUVA) fail. The response rates and duration of response are dependent on the stage of the disease. A systematic review of TSEBT as monotherapy in 952 patients reported complete response rates of 96% in stage IA, IB and IIA disease. Despite this, the 5-year relapse-free survival rates were only 10–23% [7].

The standard dose for TSEBT is 30–36 Gy as endorsed by the European Organisation for Research and Treatment of Cancer (EORTC) and the American Association of Physicists in Medicine guidelines [8, 9]. The original Stanford schedule delivered the treatment over a 9–10-week period although this has been truncated in the more commonly used UK schedule of 30 Gy in 20 fractions over a 5-week period [6]. In recognition of the palliative nature of TSEBT, there has been growing interest in reduced dose schedules with favourable toxicity profiles. Whilst doses as low as 4 Gy in four fractions have been investigated, the duration of remission is short [10]. In a recent report, however, patients treated with 10 to <20 Gy and 20 to <30 Gy were found to have similar overall response rates (>50% improvement) and relapse-free survival rates to patients treated with conventional doses of 30–36 Gy [11].

The aim of TSEBT is to treat the entire target volume, which comprises the epidermis, adnexal structures and dermis to a uniform dose. The EORTC recommendations are that the 80% isodose should be at least 4 mm deep to the surface of the skin, and that the dose at 20 mm depth should be less than 20% of the maximum dose at the skin surface [8]. There are a large number of different treatment techniques used to deliver TSEBT, the most common of which is the modified Stanford technique. This involves treating the patient standing in six positions holding onto a frame for stability (Figure 24.17). The distance between the linear accelerator and the patient needs to be at least 3 m. At this distance, the beams are angled approximately 20° above and below the central axis to deliver a reasonably uniform dose distribution. With this technique, the typical variation in dose at the skin surface is ±10% dropping to ±5% at 3 mm depth [9].

Despite this being described as the ‘optimal’ technique, there is inherent shielding of the scalp, perineum and soles of the feet which may require additional treatment. Conversely, some areas such as the wrists, ankles and ears may require shielding due to higher doses being received; shielding may also be required in previously treated areas. Sensitive areas which are spared from involvement with mycosis fungoides such as the nail beds and testicles can be shielded with lead fingernail shields and a cricket box, respectively. Custom-made lead-lined goggles are also used to shield the eyes which can be treated afterwards with superficial X-rays if there is involvement of the eyelids.

The side effects are related to the dose given, with an increased chance of toxicity with standard doses of 30–36 Gy [12]. The most common acute complications of standard dose TSEBT are erythema and moist desquamation which can be severe in patients with erythroderma. Temporary loss of fingernails and toenails also occurs if these are not shielded. Long-term side effects include xerosis and an inability to sweat properly for 6–12 months. Due to concern over possible skin atrophy and potential necrosis there is a reluctance to offer more than two conventional courses of TSEBT in a patient's lifetime.

Other lymphomas (see Chapter 139)

The technical approach to radiotherapy planning for other types of skin lymphoma is similar to that outlined earlier for individual patches, plaques and tumours of mycosis fungoides. A brief commentary on radiotherapy for specific histological subtypes is provided below.

Other cutaneous T-cell lymphomas

The approach to radiotherapy for primary cutaneous anaplastic large cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma is similar. Patients presenting with solitary or localized disease can be treated with radical radiotherapy with a recommended dose of 40 Gy in 20 fractions [13]. Lower doses may be equally effective but there are no published data. Systemic therapies should be considered for patients with multiple lesions, although short palliative radiotherapy schedules can be useful. Primary cutaneous CD4+ small or medium-sized pleomorphic T-cell lymphoma typically presents with a solitary nodule on the head and neck region which can be treated with surgery or radiotherapy.

Other cutaneous T-cell lymphomas (CTCL) including cutaneous γ-δ T-cell lymphoma, aggressive epidermotropic CD8-positive T-cell lymphoma, and extranodal natural killer T-cell lymphoma, nasal-type, which can occasionally present in the skin, have in common an aggressive clinical course with poor survival despite multiagent chemotherapy.

Cutaneous B-cell lymphoma

The EORTC published consensus recommendations for the management of cutaneous B-cell lymphoma (CBCL) in 2008 which were largely based on expert opinion due to lack of available evidence [14]. In the World Health Organization (WHO)–EORTC classification, three main types of CBCL are described. Primary cutaneous follicle centre lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are indolent conditions with 10-year survival rates in excess of 90%. The EORTC recommend a dose of 30 Gy with a margin of 1–1.5 cm of uninvolved skin. In contrast, primary cutaneous diffuse large cell lymphoma, leg type, is an aggressive lymphoma typically affecting the elderly with frequent involvement of extracutaneous sites. As a result, systemic chemotherapy is indicated followed by radiotherapy to the lesion with generous margins of 2–5 cm.

Acute radiation reaction (acute radiodermatitis) (Figures 24.18a–c and 24.19a–c)

Radiation works by damaging clonogenic cells, both benign and malignant, and the damage is expressed at the next cell division, when the cell either dies or repairs sublethal damage. Tissues with a rapid turnover such as the epidermis and mucosal endothelium therefore show radiation damage soon after treatment, and this is the ‘acute reaction’. For the treatment to result in cure, the tumour must be unable to repair this damage [1,2].

In acute radiodermatitis, histopathology shows oedema and sparseness of connective tissue beneath the epidermis. There may be flattening and loss of epidermal rete ridges with separation of the elastic tissue from the basal layer. Capillary endothelium may be hypertrophic and congested capillaries a feature. Haemorrhage and thrombosis are often observed. Special stains may show subtle changes in the DNA–RNA structure of epithelial cells as early as the third day [1, 2]. During the healing phase, the patchiness of the pathology is a striking feature. Atrophy may be bordered by epidermal hyperplasia, pigmentation is very irregular, and blood vessels are of variable size and shape; deeper vessels may be fibrosed. Normal tissue repair occurs when normal clonogenic cells on the basement membrane, which have either not received damage or have repaired sublethal damage, repopulate the basement membrane and re-cover the epithelium [3].

In a commonly used regimen, where the patient attends at daily intervals for five doses of treatment, the irradiated skin starts to redden 5–7 days after the first treatment, because of increased vascularity and inflammation associated with cell damage. Subsequent doses add to the reaction, which proceeds through dry and sometimes moist desquamation and scabbing, usually reaching a height of discomfort at 3–4 weeks after treatment finishes; it then settles over the next 2–3 weeks with re-epithelialization, which begins in the perifollicular areas and proceeds as cell colonies coalesce to cover the denuded surface.

If the skin is previously unbroken or the tumour nodular, treatment may be followed by no more than a very mild erythematous reaction with little discomfort for the patient. The acute reaction is more painful if there is ulceration and scabbing before treatment commences. The larger the surface area of the tumour and therefore the treatment field, the longer the healing takes; even so, healing is commonly virtually complete by 6 weeks after the end of the course. The brisker the treatment, i.e. the larger the dose and the shorter the time over which it is given, the more marked the acute reaction is likely to be, as there is less opportunity for normal tissue repair between treatments. Individual skin reactions vary, and those who burn in the sun tend to have a brisker reaction to X-ray treatment. Occasionally, healing may be complicated by secondary impetiginization, especially on the face.

If the exit beam passes through mucosa, a patch of mucositis of similar size to the treatment field will ensue. This reaction usually occurs earlier and is of much shorter duration than the skin reaction, and heals completely without long-term sequelae. The nasal mucosa may swell and occasionally bleed, with the feeling of a blocked nose; in the mouth, a sore patch may make eating uncomfortable for a few days. Although protective lead can be used to protect structures beyond the inner mucosa, such as the gums and the nasal septum, the mucosa just beneath the cancer cannot be protected.

It is unusual to see acute radiation reactions with diagnostic imaging but it can occur with fluoroscopy. Both dose and length of the diagnostic procedure are important causal factors. Balter et al. have comprehensively reviewed this [4].

Management

The natural history of the acute reaction cannot be modified, but the patient can avoid making the reaction worse. The area should be left open to the air as far as possible and protected from trauma, extremes of heat or cold, irritation with medicated creams or ointments, physical rubbing or vigorous and repeated washing, all of which can damage the regenerating clonogenic cells and result in ulceration. Steroid creams are also best avoided. Patients are warned to seek advice if signs of infection develop. Once the treated area is dry and scabbed, normal washing can resume. The mucosal reaction must be endured, although soft paraffin and/or a simple mouthwash helpful it may provide relief and if the patient is having excessive nasal crusting, simple saline nasal douches may make the patient more comfortable.

Late radiation reaction (chronic radiodermatitis) (Figures 24.20 and 24.21)

Tissues with a slow rate of cell division such as subcutaneous fat, fibrous tissue and small blood vessels will not show radiation effects until months or years after treatment. At 6 months, treated skin is often slightly paler or pinker than adjacent untreated skin; with the passage of time, sequelae usually appear, with late appearances established at 5–10 years. The irradiated skin may show pallor or increased pigmentation, with variable atrophy, telangiectasia, fibrosis and loss of appendageal structures. With time, the blood supply of the treated area may become compromised, resulting in ulceration either spontaneously or after trauma; such ulcers often heal spontaneously, however [5].

The fundamental histopathology of chronic radiodermatitis is fibrosis and occlusion of the cutaneous vasculature with varying degrees of homogenization of dermal connective tissue. Residual vessels may be enormously dilated. Bizarre, large, stellate fibroblasts may be seen in the dermis. Fibrosis of the deep dermis and subcutaneous tissue may occasionally occur after megavoltage radiotherapy [6]. The changes in the epidermis vary from simple atrophy to acanthosis and extreme dyskeratosis. There is usually loss of adnexa such as hair follicles.

The late cosmetic result varies and may reflect the underlying damage caused initially by the tumour as well as the patient's skin type. In one study of 339 patients, telangiectasia, pigmentation and fibrosis were directly related to increasing size of field needed for treatment rather than the treatment regimen used [7]. The late cosmetic result is also less good if the patient has had repeated cryotherapy to the area (authors’ personal observation) or been left with a poor surgical scar. Chronic radiation change may sometimes be difficult to distinguish from tumour recurrence.

Ischaemic necrosis following radiotherapy should rarely be seen when modern techniques of dose fractionation are used. Radionecrosis typically occurs 1–2 years after treatment and is often precipitated by trauma or infection. Excision and grafting may provide the only satisfactory treatment of extensive radionecrosis, although small areas may slowly heal with conservative management [5].

Induction of skin tumours within irradiated fields is very rare indeed, as would be expected with the latency for this and the average age of the patient receiving radiotherapy for skin cancers.

Tumour recurrence after radiotherapy

BCC and SCC are not always cured by radiotherapy [1, 2, 3], especially if the patient has had prior treatment with multiple modalities [4]. Ulceration lasting more than 6 months after therapy usually means persistent tumour. Some authorities suggest that one reason for avoiding primary radiotherapy is that surgical salvage is more difficult after treatment failure, but if the patient is referred on at an early stage, excision of the irradiated skin and grafting is usually possible. Mohs surgery may give the best results in these cases [4]. As with surgical treatment, radiotherapy for recurrent BCC has a higher relapse rate. Age, immunosuppression and treatment modality are also important as well as size of tumour for recurrence [5].

Re-treatment with radiation is not usually offered, because the primary is by definition relatively radio-resistant. There is an increased risk of radionecrosis if normal tissues, which may have already received a ‘tolerance dose’, are exposed to further radiation. However, in practice, radiotherapy has been given successfully in these circumstances with acceptable cosmetic results, especially if there has been a sufficient time interval between the two radiotherapy treatments [6]. Occasionally, it is reasonable to offer treatment to persistent tumour at the edge of a previous radiotherapy field, when a small degree of overlap may be acceptable; although the risk of a small area of necrosis will be higher, this strategy is often acceptable to the patient, and successful.

Radiation-induced tumours

There is evidence that the risk both of BCC and of SCC is increased in areas of skin previously irradiated for benign or malignant disease including Hodgkin disease, breast cancer, acne, ankylosing spondylitis and tinea capitis [1, 2].

BCCs of the scalp may not present until 50 years after X-ray epilation for ringworm. Such tumours are much more rarely seen since the virtual abandonment of radiotherapy for benign diseases, the development of more sophisticated radiotherapy machinery and advances in the understanding of radiobiology. It has not, however, been possible to demonstrate any precise quantitative relationship between the development of skin cancers and the amount of radiation received on the skin surface, nor is it known what total dose or fractionation regimen would be most carcinogenic.

Although a greater knowledge of the limitations and effectiveness of radiation should prevent the occurrence of late radiation damage including carcinogenicity, the long latent periods involved warn against early complacency [3, 4, 5].

As the numbers of childhood cancer survivors increases, there is some evidence for an increased incidence of BCC developing within irradiated skin sites [6], but this is not confirmed by all studies [7]. As most of these children will also have had treatment with chemotherapy, the aetiological factors causing their second malignancy cannot be easily disentangled.

Management

Most radiation-induced tumours should be excised. However, where there is no radiation damage evident on the skin, a subsequent radical dose of radiotherapy can normally be tolerated [8].

Rare tumours associated with previous irradiation

Atypical fibroxanthoma (see Chapter 137) (syn. pseudosarcoma of the skin)

This tumour, seen particularly in fair-skinned males who have suffered actinic damage, may also follow radiation damage [9, 10, 11].

Radiation-induced sarcoma (see Chapter 137)

Radiotherapy-induced sarcomas make up an estimated 5% of all sarcomas and occur in less than 0.2% of patients who have had radiotherapy [12, 13]. Children are more susceptible to developing radiation-induced cancer [14]. There can be a long latent period with sarcomas appearing 5–15 years or even longer post-treatment [15, 16].

Post-irradiation sarcomas of both soft tissue and bone are characteristically high grade and include undifferentiated pleomorphic sarcoma (previously known as malignant fibrous histiocytoma), spindle cell sarcoma, osteosarcoma, leiomyosarcoma and angiosarcoma, the latter being especially associated with radiotherapy for breast cancer [15].

Development of sarcoma appears to be related to exposure to kilovoltage rather than megavoltage radiotherapy and to receiving higher doses of radiotherapy. It is also associated with a range of genetic syndromes which may predispose to cancer development such as Li–Fraumeni syndrome.

Diagnosis and investigation are as for primary sarcomas, including a carefully planned biopsy.

There is evidence that prognosis is worse for radiation-induced sarcomas compared to primary sarcomas [16]. Surgery and chemotherapy are the primary treatment modalities with re-irradiation usually avoided.

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Mycosis fungoides and other lymphomas

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Acute radiation reaction (acute radiodermatitis)

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Tumour recurrence after radiotherapy

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Radiation-induced tumours and rare tumours associated with previous irradiation

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