8. Radiotherapy

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Introduction

Radiotherapy (RT) is an effective treatment modality for keratinocyte cancers (KCs), including all stages of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). It is used in definitive (curative) treatment, postoperative treatment, in the management of recurrent or metastatic disease, and in palliative treatment.

For early-stage disease, results are comparable to surgery.[1]

Mechanism of action and modalities

Radiotherapy involves exposure of the target tissue to ionising radiation (x and γ rays, photons, β rays, electrons, particles) delivered by external-beam RT (EBRT) or brachytherapy.[2][3][4][5][6][7][8][9]

Radiotherapy works mainly through its effect on deoxyribose nucleic acid (DNA), which is very sensitive to radiation. Cancer cells have poor DNA repair capacity and die following damage from RT, while normal cells have a better DNA repair capacity,[10] repairing most RT damage to their DNA within 6 hours after a single treatment with an appropriate dose. In a mixed population of cancer cells and normal cells, RT can spare normal cells while eradicating cancer cells. [10]

External-beam RT modalities include superficial x-ray therapy,[11][12] orthovoltage radiotherapy, and megavoltage therapy from linear accelerators. Electronic brachytherapy is actually a type of EBRT.[13][14]

Brachytherapy is the use of isotopes applied directly to the tumour as a surface treatment or implanted into the tumour.[15] It can be applied using a sealed or unsealed source. Sealed sources are isotopes sealed within non-radioactive containers, such as a temporary high-dose rate source (e.g. iridium-192 source in a titanium casing) or a permanent low-dose rate source (e.g. iodine-125). The casing allows for accurate dosimetry and safety for patient and staff. Unsealed sources include topical rhenium-188. Brachytherapy deposits a high dose at the interface between the source and the tumour, with a rapid fall-off, thereby minimising the dose to deeper normal tissues. There is some evidence for better cosmesis with brachytherapy compared with EBRT.[16]

The selection of RT modality depends on the depth of penetration required to treat the lesion adequately. Superficial x-ray therapy is suitable for lesions with a depth of up to 5mm. Lesions with greater depth can be treated with modalities that achieve greater penetration, such as orthovoltage radiotherapy, megavoltage electrons, or photons produced by a linear accelerator.

The effective radiation field encompasses the tumour plus a normal tissue margin (the perimeter of normal-appearing skin adjacent to the skin cancer). The normal tissue margin is usually 0.5cm width for small well-defined BCCs and well-differentiated cSCCs, but 1–1.5cm for larger ill-defined BCCs and more aggressive cSCCs. The margin depends on the quality of patient immobilisation and the modality (e.g. electrons have a wider penumbra than the photons delivered in superficial x-ray therapy.)

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Recent advances

Radiotherapy has significantly improved in the last few decades in two main areas: greater conformality of dose to tumour volume and more precise fractionation. These improvements have led to higher cure rates and reduced toxicity to normal tissue.[17]

Significant recent improvements in RT technology have enabled greater conformality of dose to tumour volumes and reduced conformality to normal tissue volumes. Improved understanding of radiobiology has led to understanding the importance of total dose and dose per fraction. Proper fractionation results in tumour control but minimal late effects in surrounding normal tissue. However, hypofractionation is effective in the treatment of KCs.[18][19][20] Hypofractionation is ideal for patient for whom function and cosmesis are not high priorities, and for whom attendance at a fully fractionated course of RT would be difficult due to comorbidities.[21][20][22][23]

Newer modalities such as volumetric modulated arc therapy enable definitive RT for large areas of skin field-cancerisation,[24][20] increasing the indications for RT in skin cancer.

Advantages of radiotherapy

Because RT can conserve tissue, it may achieve superior functional and cosmetic outcomes for cancer treatment in cases where surgical treatment is likely to result in bulk volume tissue loss, numbness or paralysis (e.g. due to facial nerve sacrifice). Cases where tissue conservation may be an advantage include treatment of cancers of the lip or eyelid commissures,[25] nasectomy or resection of nasal ala.

Radiotherapy does not require anaesthetic or excision. It also avoids issues that can complicate surgery, such as tissue tension causing poor healing, skin graft survival, and anticoagulant therapy. As no tissue is lost, RT margins can be greater than surgical margins.[26]Back to top

Disadvantages of radiotherapy

Disadvantages of RT include the need for repeated treatments (fractionation). If too much RT is given in a single treatment (fraction), the repair capacity of normal cells is exceeded, and dead cells are eventually replaced by fibrous tissue. Late effects after RT can include hypopigmentation and sometimes induration in the RT field, causing tissue retraction, poor function and poor cosmesis. To minimise the risk of these late side effects, RT needs to be given in small doses (fractions).

In general, small doses (e.g.1.8–2.0 Gy daily) of RT result in greater survival of normal cells, and therefore superior function and cosmesis, compared with larger daily doses (>2.0 Gy daily). However, not all studies support a difference in cosmesis with fraction size.[27]

Delivering small daily doses of RT requires a greater number of treatments and therefore more visits to a RT facility to achieve an effective curative dose, compared with large daily doses. This may be problematic for some patients.

Standard curative dose schedules for treatment of small lesions (<2cm) usually require fewer treatments (4–12 attendances over 1–2 weeks) compared with larger lesions, which require 15–30 treatments over 3–6 weeks.

Following RT there is no histopathology report that verifies the cancer type or confirms that it has been completely treated.

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Limitations of the evidence

Relatively few studies have investigated RT in the treatment of skin cancer, and there is limited high-level evidence to guide treatment decisions. Cochrane reviews of interventions for BCC, cSCC and actinic keratosis (AK) have included very few or no RCTs evaluating RT.[28][29][30]

The evidence to support RT is based on data from retrospective studies, usually conducted in a single institution. Very few data are available from Australian studies, despite the high burden of KC in Australia.

In the absence of a large body of high-quality evidence to guide the selection of RT, it is currently prescribed according to accepted relative indications and contraindications derived from common sense (Table 6).[31]Table 6. Relative indications and contraindications of radiotherapy for keratinocyte cancers

Relative indications Relative contraindications
Tumour factors Sites or lesions where tissue conservation is crucial and surgery would result in major loss of function (e.g. tip of nose, lateral eyelid commissure, lip commissure, site proximal to facial nerve, large superficial lesions, PNI)

Multiple lesions (especially superficial lesions) when impractical to excise

Invasion into bone or joints(a)

Sites with poor vascularity, lower leg skin overlying anterior tibia or malleoli

Treatment factors Circumstances where repeated surgery would be burdensome Previous RT at site

Sites where RT would result in unacceptable hair loss

Patient factors Unfit for surgery

Unacceptable anaesthesia risk

Anticoagulant therapy

Unable to tolerate multiple surgical procedures (e.g. due to ageing)

Tendency to keloid development

Patient preference

Immunosuppression (e.g. OTR, patient with CLL, patient on long-term corticosteroid therapy)

Young age (increased risk of RT-induced malignancy, prioritisation of cosmesis)

Naevoid BCC (Gorlin’s syndrome)(naevoid BCC syndrome) an autosomal dominant syndrome characterised by multiple BCCs (b) (increased risk of in-field BCCs)

Limited access to RT facility

Active connective tissue disorders (e.g. scleroderma; increased risk of acute and late RT-related effects)

Collagen vascular disease

BCC: basal cell carcinoma; CLL: chronic lymphocytic leukaemia; OTR: organ transplant recipient; PNI: perineural invasion; RT: radiotherapy.

(a) Cartilage involvement is not an absolute contraindication. Radiotherapy must be given cautiously in larger pinna lesions with extensive, inflamed or painful cartilage invasion. (b) excepting specific lesions for which RT is indicated. Sources[25][32][33]
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Misunderstandings of RT

The lack of high-quality evidence from well-designed prospective clinical trials has allowed misconceptions about RT in skin cancer to persist. These include the belief that RT should not be used for skin lesions below the knees, that radiation-induced cancer is common, and that only patients over 70 years old should have definitive radiotherapy for skin lesions. There are no prospective data to support any of these claims, yet they are perpetuated in some guidelines.[34]

A recent literature review reported the rate of RT-induced in-field cancer to be 1 in 1000 every 10 years[32]

The belief that the use of RT should be restricted to older patients is based on historical observations of poor long-term cosmetic outcomes (e.g. hypopigmentation, telangiectasia, cicatrisation and in-field fibrosis) associated with poor-quality RT, including hypofractionated treatment. These effects occurred during an era when RT was prescribed by clinicians other than trained radiation oncologists and large doses were used. Current knowledge of the radiobiological association between fraction size and chronic inflammation with fibrosis, and highly developed specialist training practices, have significantly improved cosmetic outcomes.

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References

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