key: cord-0897681-a4fzr23q
authors: Veness, Michael
title: Hypofractionated radiotherapy in patients with non‐melanoma skin cancer in the post COVID‐19 era: Time to reconsider its role for most patients
date: 2020-05-27
journal: J Med Imaging Radiat Oncol
DOI: 10.1111/1754-9485.13070
sha: 3b1ad12af16170d57f022cc2e044c6d1cd91dc38
doc_id: 897681
cord_uid: a4fzr23q

The most frequent cancer worldwide is skin cancer, occurring at epidemic rates in countries exposed to high levels of chronic ultraviolet radiation such as Australia and New Zealand (ANZ). Australia has the highest incidence of non‐melanoma skin cancer (NMSC) in the world. NMSC is predominantly a cancer of the middle aged or elderly and accounts for considerable consulting and treatment time in most radiation oncology departments. Many patients also suffer from medical co‐morbidity, an important factor in any treatment decision.

The most frequent cancer worldwide is skin cancer, occurring at epidemic rates in countries exposed to high levels of chronic ultraviolet radiation such as Australia and New Zealand (ANZ). Australia has the highest incidence of non-melanoma skin cancer (NMSC) in the world. NMSC is predominantly a cancer of the middle aged or elderly and accounts for considerable consulting and treatment time in most radiation oncology departments. Many patients also suffer from medical co-morbidity, an important factor in any treatment decision.

Radiation oncologists (ROs) within ANZ manage patients with NMSC in the definitive, adjuvant or palliative settings. Many treatments are localised and relatively superficial (primary site) but also can involve regional (usually adjuvant) and occasionally noncutaneous palliative sites. No other cancer is so effectively treated utilising such a variety of techniques using ionising radiotherapy (RT), delivered by either external beam

This article is protected by copyright. All rights reserved (superficial/megavoltage photons or electrons) or brachytherapy [(BT) low dose, high dose, electronic brachytherapy]. 1 Whatever modality is utilised NMSC is radioresponsive and in most clinical scenarios patients treated with definitive RT (whatever technique) can expect local control rates of > 90-95%. Younger patients of good performance status (< 70 years old) have often been treated with longer course RT utilising smaller doses per fraction (e.g. 55-50 Gy in 2-2.5 Gy) aiming to achieve the best local control and minimise late cutaneous side effects (e.g. infield hypopigmentation, epidermal atrophy, telangiectasia).

In older patients (70-80 years old) the late effects are less concerning with the aim to decrease the duration of treatment utilising fraction sizes of 3-4 Gy over 2-3 weeks (e.g. 40-45 Gy in 10-15 fractions). Most ROs would consider delivering fraction sizes ≥ 3 Gy as hypofractionation with published ranges of 3-20 Gy fraction sizes associated with a concomitant decrease in total dose as dose/fraction increases. Despite these variations in many cases a similar biological effective dose (BED), assuming an α/β = 10, is delivered.

In elderly (> 80 years old) and/or poor performance patients extended course treatment is often inappropriate. Many have advanced and inoperable NMSC that if left untreated experience local morbidity. In these patients shorter course hypofractionated RT, delivered second daily or once weekly is a highly effective modality with acceptable and self-limiting treatment related toxicity. 2 The COVID-19 global pandemic has presented an unprecedented challenge in the way we manage cancer patients. In an attempt to limit contact between staff and patients radiation oncology departments have identified low-risk patients, such as those with ductal insitu breast cancer (DCIS), basal cell carcinomas (BCC) or low risk squamous cell carcinomas (SCC), that could potentially have their RT safely deferred for a number of months (2-3 months).

Organisations such as hospitals and specialist Colleges/Societies have released guidelines and recommendations to aid clinicians in decision making.

Strategies for patients with NMSC include delaying consults and/or commencing RT, or considering alternative options e.g. excision. Unfortunately, the COVID-19 impact on other specialties (e.g. dermatology) is similarly profound and in many cases there are no easily accessible alternative treatments available as these specialities are also prioritising

This article is protected by copyright. All rights reserved resources. To compound this, many patients, especially those that are older, are selfisolating or finding difficulty in arranging consultations are thereby possibly delaying an early diagnosis (i.e. biopsy) and treatment (i.e. simple excision). Elderly nursing home patients are often in complete lockdown and in many cases are unable to be accessed or be sent for medical review. 

This article is protected by copyright. All rights reserved Evidence of a dose-response relationship in NMSC is weak or similarly whether BCC or SCC respond differently. Many studies report summary results for differing histopathology (BCC vs SCC), subsites (head and neck vs other) and settings (definitive vs adjuvant) with dose fractionation schedules independent of these differences.

Large single fractions are an extreme form of hypofractionation for treating patients with NMSC with concerns raised regarding late toxicity such as skin/soft tissue or cartilage necrosis. However in a UK study of 1005 BCC/SCC (95% 1.5-3 cm in size, mean age 68 yrs) treated with one single fraction (either 18 Gy, 20 Gy or 22.5 Gy) the incidence of late skin necrosis (at 10 years) was 6% with most cases healing spontaneously. Local recurrence rates were 4% and subsequently a fraction size > 20 Gy was not recommended because of an increasing risk of skin necrosis. 4 It would not be unreasonable to consider a single fraction of 15-18 Gy as a reasonable option in many older unwell patients with a NMSC, accepting the extra time needed to deliver this larger fraction.

Beyond the role of definitive RT is that of adjuvant RT often in the setting of a positive/close margin or perineural invasion. There is an acknowledged lack of consensus on the clear indications and benefits of adjuvant RT in many settings. The literature suggests that many patients with close or margin positive NMSC (especially BCC) undergoing reexcision do not harbour residual NMSC, or will recur without further treatment, and consequently many patients with incompletely excised BCC, and even low risk SCC, could safely be observed and offered treatment if local recurrence occurs. Many will experience the competing risk of medical co-morbidity which is an important consideration in any management decision, perhaps more so in the adjuvant setting where there is no symptomatic disease present. If adjuvant RT is recommended the effectiveness of hypofractionation is likely to be similar to that of definitive RT and should be considered an option.

A recent (pre-COVID-19) ASTRO evidence based clinical practice guideline recommended hypofractionation (2.1-5 Gy fraction sizes using 8-20 fractions) schedules, as options, in both the definitive and postoperative settings for NMSC, acknowledging the low level of published evidence. 5 The evidence to support an excellent local control rate and in-field

This article is protected by copyright. All rights reserved And should not many adjuvant patients be observed and treated expectantly ( Table 1 )?

There will always be exceptions, for example larger RT fields/target volumes that encompass sensitive neural structures when treating patients with perineural invasion, or high-risk lower lip SCC where the aim is curative and to achieve the best long term function (oral competence), in which cases 20 or 25 fractions may be justified, but for many referrals this should not be the case.

Each RO will always remain the advocate for their patients but with possible lengthy waiting times ahead this may be challenging. More so than ever the proven role of hypofractionation in NMSC (and in many other cancers) in an era of post COVID-19 limited resources is increasingly relevant. This approach should not be seen as delivering a less optimal treatment. 

This article is protected by copyright. All rights reserved 

Current role of radiotherapy in non-melanoma skin cancer

Hypofractionated radiotherapy in older patients with non-melanoma skin cancer: Less is better

Efficacy of hypofractionated radiotherapy in patients with non-melanoma skin cancer: Results of a systematic review

Single fraction radiotherapy for small superficial carcinoma of the skin

Definitive and postoperative radiation therapy for Basal and Squamous cell cancers of the skin: An ASTRO clinical practice guideline

Accepted Article