Radiotherapy (RT) modalities and approaches currently under investigation for use in the treatment of keratinocyte cancer (KC) include volumetric modulated arc therapy (VMAT) and the combination of RT with adjuvant immunotherapies.
Volumetric modulated arc therapy (background)
Intensity-modulated RT occurs when multi-leaf collimators (MLCs) within the linear accelerator (linac) gantry move in real time across the RT beam, so modulating the intensity of the beam during treatment. This is an advancement on three-dimensional conformal RT in which the beam comes in ‘blocks’. Intensity-modulated RT allows the dose volume to curve around structures such as volumes of tumour to be treated or organs to be avoided. This technology has enabled increased conformality of dose, which allows for dose escalation to tumour and dose de-escalation to normal tissue volumes, thereby increasing the therapeutic ratio.
Volumetric modulated arc therapy represents a further stage of evolution towards complete dose conformality. This technology can be conceptualised as the application of computed tomography to the linac. The gantry moves in a continual arc, capable of changing the rotational velocity. Other aspects can change; the dose rate of RT coming out of the machine, and the velocity of the MLCs, leading to great precision. This type of external-beam RT is challenging brachytherapy as the ultimate conformal therapy.
Overview of evidence (non-systematic literature review)
Volumetric modulated arc therapy
The rotating gantry now allows difficult-to-treat volumes to be adequately irradiated without damage to nearby dose sensitive structures and can be combined with systemic therapies without significant dose limiting toxicities. It also allows large convex areas to be treated, and these include areas of actinic change in which RT is effective.Results from clinical trials evaluating VMAT in the treatment of KCs are expected to become available from around mid-2019.
Tumour mutation burden
Tumour mutation burden (TMB) is associated with better survival in some skin cancers, such as Merkel cell carcinoma and melanoma. Immunotherapy works better in cancers with high mutational load. Adding RT to immune therapy in the treatment of melanoma has been associated with a greater response.
The TMB of KCs is the highest of any cancer type. Accordingly, the combination of RT with immunotherapy in high-risk KC may increase the response. This hypothesis is likely to generate a high volume of radiobiological research.
No data are currently available from clinical trials evaluating the effect of TMB on outcomes of RT for KCs.
Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of head and neck cancer in combination with RT. Inactivation of EGFR is associated with increased radiosensitivity. In the palliative setting, cetuximab as monotherapy or in combination with RT can achieve durable control of advanced cutaneous squamous cell carcinoma (cSCC).
Cetuximab was associated with statistically non-significant benefit for overall survival and disease-free survival, compared with platinum-based chemotherapy, in a retrospective observational series in which patients received RT with either concomitant platinum-based chemotherapy or cetuximab as definitive (48%) or adjuvant (52%) treatment for locally advanced cSCC of head and neck.
Acne-like rash is one of the more serious side effects of cetuximab therapy.Erlotinib, another EGFR inhibitor, increases local control in cSCC with RT, as does gefitinib.
Vismodegib is approved by the Australian Therapeutic Goods Administration for the treatment of basal cell carcinoma (BCC). It targets the hedgehog signalling pathway (which is upregulated in 90% of BCCs) and acts as a cyclopamine-competitive antagonist of the smoothened, frizzled class receptor (SMO).
Vismodegib shrinks BCCs. Case reports have documented that, when combined with RT and surgery, vismodegib treatment can make BCC resectable or amenable to being encompassed in an RT field, or even achieve durable and acceptable stable disease.
Vismodegib is particularly helpful for the treatment of patients with naevoid BCC (Gorlin’s syndrome)(naevoid BCC syndrome) an autosomal dominant syndrome characterised by multiple BCCs, in which RT is generally avoided because it can predispose to more in-field BCCs.
Other radiotherapy modalities
Proton and neutron therapies may also improve therapeutic ratio in locally advanced skin cancer by achieving greater conformality.
A recent matched pair analysis reported that the outcomes of brachytherapy were equivalent to those of Mohs micrographic surgery in the treatment of early-stage KC.
- Radiotherapy – Introduction
- Radiotherapy with or without surgical treatment for keratinocyte cancer
- Radiotherapy for basal cell carcinoma
- Radiotherapy for cutaneous squamous cell carcinoma
- Radiotherapy for regional (nodal) metastatic disease (non-distant)
- Radiotherapy for actinic keratosis and cutaneous squamous cell carcinoma in situ
- Radiotherapy for keratoacanthoma
- Management of side effects of radiotherapy
- Radiotherapy – health system implications and discussion
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