Review articleCharacterizing the phenomenon of radiation recall dermatitis
Introduction
Radiation recall is well recognized as a concept in the field of radiation oncology but rarely clinically seen. It represents the development of an inflammatory reaction throughout a previously irradiated area, precipitated by the administration of certain drugs. The drugs are often, but not exclusively, intravenous cytotoxics (cf. Section 6). There may be a considerable time period between the radiation exposure and the administration of a recall-triggering drug (cf. Section 3).
The phenomenon was first described at the Childrens Medical Center in Boston in association with actinomycin D, when D'Angio and co-workers [11] reported that:
Actinomycin D therapy alone can reactivate ‘latent’ radiation effects in normal tissues...In skin previously irradiated but normal in appearance an erythema may develop during actinomycin D therapy, identical in type to that produced by roentgen irradiation. This response is sharply restricted to the areas previously treated by X-rays. The severity of the reaction varies from a mild reddening to pronounced desquamation.
In the intervening 40 years, many other drugs have been associated with radiation recall reactions (Table 1), but the recall itself remains a loosely characterized and poorly understood phenomenon. When cases occur physicians often have to decide between running the risk of further recall reactions or discontinuing therapeutically useful drugs with little published data upon which to base their decisions. This review attempts to draw together what is known about the phenomenon, based largely on what has only been described in case reports, and what can be hypothesized given the available evidence. The vast majority of cases described in the literature involve dermatitis as the overt manifestation of radiation recall. To limit the discussion to an unequivocal phenomenon as much as possible, the clinical data reviewed will therefore concentrate almost exclusively on radiation recall dermatitis (RRD). It is important to note however, that radiation recall pneumonitis, oesophagitis and mucositis have also been described [5], [18], [35], with appropriately serious clinical consequences.
Section snippets
Towards a tighter timing definition
No formal grading system for RRD exists. Where reported cases of RRD have been described in enough detail to analyse (Table 2), we have graded each reaction using a scale based on the RTOG Acute Radiation Morbidity Criteria for skin (taking into account the terms ‘pruritus,’ ‘vesiculation’ and ‘urticaria’ common in the descriptions of RRD but not contained in the original RTOG system):
- Grade 1 (mild):
Erythema±pruritus±dry desquamation
- Grade 2 (mild-moderate):
Grade 1 with pain, oedema, urticaria
Range of timing intervals
The longest recorded interval for any recall phenomenon was that reported by Burdon et al. [5] in a man with adriamycin-induced stomatitis 15 years after radiotherapy treatment of a palatal sarcoma. The longest interval between radiotherapy and drug triggering a recall dermatitis is 7 years [26]. In this patient, however, the previously irradiated skin showed significant late radiation change prior to drug administration. In addition, the recall reaction only manifested itself after six cycles
Incidence
There is little published directly on the incidence of RRD, as cases tend to be described with no information on the numbers treated similarly who have not developed RRD. Even if the background information is provided, most reports include only a single case of RRD, therefore overestimates of the incidence are likely. Certain drugs do, however, seem to be associated with RRD more frequently than others. Given these caveats, estimates of incidence may be made for individual drugs.
At one extreme
Radiation characteristics
The majority of case reports on RRD specify the radiation dose to the tumour, rather than to the skin where the RRD is later manifest. The tumour dose in cases of RRD ranges from 10 to 61.2 Gy (Table 2). Even allowing for the uncertainty regarding skin dose, a lower estimate of the radiation dose required for RRD based on this information remains inappropriate to calculate. This is because the effect of time elapsed from radiation exposure also has to be considered. A radiation dose necessary
Drug characteristics
The majority of drugs (Table 1) reported in association with RRD have been given as monotherapy. When drugs, notably chemotherapy drugs, have been given in combination, no particular interactions either increasing or decreasing the risk of RRD have been documented. The features that the drugs in Table 1 share that explain their association with RRD are unknown. Interestingly, RRD has never been reported in association with a number of commonly used chemotherapy drugs, such as cyclophosphamide
The nature of the skin reaction
Pronounced acute radiation reactions during radiotherapy are not required for subsequent RRD, indeed their existence is unusual [34], [43]. Moreover, patients having experienced RRD may have other areas of skin irradiated subsequently with no abnormal radiation reaction [36]. There is no known association between the development of RRD and any subsequent late skin reactions.
The speed of onset of RRD reactions is particularly interesting (Table 2). The range with intravenous drugs is from a few
Rechallenge with recall-triggering drugs
The majority of patients reported with RRD are not rechallenged with the RRD implicated drug, presumably due to fears about recurrence. In the literature of RRD evidence to justify or refute this is limited, but 15 patients rechallenged with their RRD-inducing drug can be confidently identified [7], [14], [15], [17], [25], [29], [30], [31], [34], [35], [38], [47]. Of these, ten showed recurrence of RRD [14], [15], [17], [25], [30], [34], but the RRD was milder than the initial presentation in
Potential aetiologies
Any viable aetiological hypothesis must be consistent with the key characteristics of RRD suggested in this review. A number of different hypotheses have been proposed for RRD although with little evidence base to support any of them. Essentially the hypotheses focus on either vascular, epithelial stem cell inadequacy, epithelial stem cell sensitivity or drug hypersensitivity reactions as the mechanism for RRD. Each will be covered in turn.
Conclusions
The ability of certain drugs to elicit inflammatory reactions in previously irradiated skin long after the initial effects of the radiation have apparently disappeared has been recognized for over 40 years.
Potential areas of confusion exist between radiation recall, radiosensitization and interference with ongoing acute radiation reactions. Guidelines to distinguish these have been proposed in this review.
The aetiology of RRD remains unknown. A number of hypotheses have been described. We have
References (47)
- et al.
Radiation reaction recall following simvastatin therapy: a new observation
Clin Oncol
(1995) - et al.
Paclitaxel-induced radiation recall dermatitis
Ann Oncol
(1996) - et al.
Radiation and chemotherapy sensitizers and protectors
Crit Rev Oncol Hematol
(1990) - et al.
Stem cell depletion: an explanation of the late effects of cytotoxins
Int J Radiat Oncol Biol Phys
(1977) Cutaneous side effects of cancer chemotherapy
Med Clin North Am
(1986)- et al.
The ‘recall effect’ in radiotherapy: is subeffective, reparable damage involved?
Int J Radiat Oncol Biol Phys
(1990) Skin reaction to vinblastine
Lancet
(1969)- et al.
Complications of irradiation related to apparent drug potentiation by adriamycin
Int J Radiat Oncol Biol Phys
(1976) - et al.
An acceptable rate of complications in combined doxorubicin-irradiation for small cell carcinoma of the lung: a Southwest Oncology Group study
Int J Radiat Oncol Biol Phys
(1978) Radiation recall induced by tamoxifen
Lancet
(1992)
Taxol and radiation recall dermatitis
Lancet
The search for therapeutic gain in the combination of radiotherapy and chemotherapy
Radiother Oncol
Cutaneous drug reactions: pathogenesis and clinical classification
J Am Acad Dermatol
Radiation-recall dermatitis with docetaxel: establishment of a requisite radiation threshold
Eur J Cancer
Adriamycin-irradiation cutaneous complications
Int J Radiat Oncol Biol Phys
Radiation recall: another call with tamoxifen
Acta Oncol
Adriamycin-induced recall phenomenon 15 years after radiotherapy
J Am Med Assoc
Side effects of chemotherapy. Case 1. Radiation recall dermatitis from gemcitabine
J Clin Oncol
Docetaxel-induced radiation recall dermatitis and successful rechallenge without recurrence
Clin Oncol
Radiation-adriamycin interactions: preliminary clinical observations
Cancer
Side effects of chemotherapy. Case 2. Radiation recall reaction induced by gemcitabine
J Clin Oncol
Potentiation of X-ray effects of actinomycin D
Radiology
Clinical and biological studies of actinomycin D and roentgen irradiation
Am J Roentgenol
Cited by (255)
Radiation recall dermatitis induced by ibuprofen
2023, Anais Brasileiros de DermatologiaRadiation Recall Dermatitis after Donor Lymphocyte Infusion for Adult T-Cell Leukemia Lymphoma Post–Allogeneic Stem Cell Transplant
2023, Practical Radiation OncologyCitation Excerpt :Its mechanism remains unknown. Camidge and Price proposed that the rarity, speed of onset, unpredictable effect, and extreme drug specificity of RRD was most consistent with an idiosyncratic drug hypersensitivity reaction.7 Irradiation may lower the inflammatory response threshold through continued low-level secretion of the inflammation-mediating cytokines.
Management of skin toxicity
2023, Palliative Radiation OncologyLate toxicities management
2023, Palliative Radiation OncologyStochastic Stomatitis: Radiation Recall Reactions in the Era of Immune Checkpoint Blockade
2023, International Journal of Radiation Oncology Biology PhysicsRadiation recall dermatitis induced by COVID-19 vaccination in breast cancer patients treated with postoperative radiation therapy
2022, BreastCitation Excerpt :In our dataset we found the highest risk of having RRD when the first dose of COVID-19 vaccine was administered within the first 30 days after treatment with postoperative EBRT. Even though there is no data regarding the specific timing for RRD development, one paper estimated that most cases occurred within 40 days Camidge et al. [18], in agreement with our results. As reported in the literature [19], we also found that the risk of having RRD did not depend on the postoperative radiation dose (dose schedule or boost addiction), age, breast reconstruction or previous chemotherapy or by a previous COVID-19 infection.