Reirradiation of Skin Tumors

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With the increase of life expectancy, there are more cases of local recurrence or in-field secondary cutaneous tumor in previously irradiated skin cancers. In most cases, due to the radiation-induced fibrosis and comorbidities associated with old age, patients have no indication for surgery or systemic treatments (e.g., chemotherapy, cetuximab). Therefore, reirradiation is the option available to try the local control of the cutaneous tumor, and consequently improve the survival. However, there are very few and heterogeneous pre-clinical studies described in literature, and the clinical reports that exist are small and retrospective revisions. This paper is a mini-review of these basic and clinical reports, and other analyses. Irradiation with curative intent is possible, but it must be aware of a decrease in tissue tolerance from previous radiation therapy, that may improve with the increased time between the two irradiations. It should also be take into account the risk-benefit, the comorbidities, the total dose, the fractionations, the irradiated volume, and the dose previously received by the organs at risk. This subject may justify a clinical trial.

Studies of RT as definitive treatment in primary and recurrent skin cancers consistently report high rates of local control despite extremely variable total doses and fractionation schedules. With the increase of life expectancy, many patients develop second primary tumors within or close to previous RT area or late in-field recurrences. Moreover, surgical options are frequently compromised by local responses (e.g. fibrosis) to the first treatment . Therefore,there are increasing request for reirradiation when other treatment options are discarded. However, reirradiation remains clinically challenging, especially with curative intent, because such treatment is thought to induce severe iatrogenic complications (bleeding, ulceration, tissue necrosis), as demonstrated in mucosal tumor reirradiation. On the other hand, preclinical data are relatively scarce, and there are no clinical data in literature to support the safety and efficacy of skin cancer reirradiation with curative doses, only small retrospective studies, regardless of doses and fractional schedules, with limited statistical power. Moreover, the capacity for longterm recovery from RT injury varies considerably among tissues and species.

Histologically, the skin is composed of three compartments: the epidermis, the dermis, and the hypodermis. The epidermis is a keratinized stratified squamous epithelium that is replaced continuously from the basal layer. The renewal cycle is about 3 weeks. The dermis is the most important layer of the skin. It provides strength, elasticity and self-renewal capacities to the skin, and contains blood and lymphatic vessels, nerve endings, hair follicles, and sweat and sebaceous glands. Most cutaneous sensory receptors are located in the hypodermis, or subcutaneous tissue. It also includes wider lymphatic and blood vessels, and fat tissue. The skin is a first defense against microbial agents and to physical and chemical compounds. It also allows regulate the temperature of the body via the sweat glands. In terms of RT delineation, the skin coat corresponds to the whole body surface in a thickness of 3-5mm.

The mechanisms involved in the genesis of radiation induced toxicity depend on the individual radiosensitivity, the tissue and cellular architecture, the total administered dose, the fractionation, and the volume irradiated. Skin has no well-defined functional subunits, but responds in a way similar to tissues in parallel. The loss of organ function after RT requires destruction of several subunits. A fleeting erythema may appear within hours of irradiation and then disappears a few hours or days later. The definitive destruction of adult stem cells by RT leads to a non-replacement of differentiated cells. Therefore, the expression of side effects appears when cells enter again in mitosis. The functional damage to the stratum corneum induced by RT starts within a mean period of 11 days and reaches maximal values after a mean of 27 days (range: 13- 75). The grade 2 radiodermatitis , or epidermal necrosis, appears in 4-5 weeks after the beginning of conventional RT (1.8-2 Gy/fraction, one fraction/day, and five fractions/ week) or after an EQD2 to the skin of 40 Gy, and disappear 1-2 months after RT (skin renewal lasting 20-45 days). An EQD2 to the skin of less than 45 Gy allows to limit the appearance of severe acute or late cutaneous toxicity.