Case report of cold-weather-induced radiation recall dermatitis after chemoradiotherapy with cisplatin
- First Online:
- Cite this article as:
- Kindts, I., Stellamans, K., Bonny, M. et al. Strahlenther Onkol (2014) 190: 762. doi:10.1007/s00066-014-0632-2
- 159 Views
The radiation recall reaction (RRR) is an inflammatory reaction that occurs in previously irradiated areas. The phenomenon is probably due to an idiosyncratic hypersensitivity reaction, in which a second agent can recall the inflammatory reaction.
This case report documents a cold-weather-induced radiation recall dermatitis (RRD). We observed a severe RRD in a patient after chemoradiotherapy treatment with cisplatin for a nasopharyngeal carcinoma, precipitated by cold temperatures, which developed 9 days after completion of therapy. In the medical literature, RRD following extreme cold temperatures seems to be a peculiar event.
Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction.
KeywordsRecall dermatitisChemoradiationCisplatinHead and neck cancerCold temperature
Fallbericht einer kaltwetterinduzierten „Radiation-Recall“-Dermatitis nach einer Radiochemotherapie mit Cisplatin
Die „Radiation-Recall-Reaktion“ (RRR) ist eine Entzündungsreaktion, die in zuvor bestrahlten Bereichen auftritt. Das Phänomen wird wahrscheinlich durch eine spezifische Überempfindlichkeitsreaktion verursacht, bei der ein zweites Agens die Entzündungsreaktion hervorruft.
Dieser Fallbericht beschreibt eine kaltwetterinduzierte RR-Hautentzündung. Wir beobachteten bei dem Patienten nach einer Radiochemotherapie mit Cisplatin aufgrund eines Nasopharynxkarzinoms eine heftige RR-Dermatitis (RRD) aufgrund kalter Temperaturen, die sich 9 Tage nach Therapiebeendigung entwickelte. In der medizinischen Literatur scheint eine RRD infolge extrem kalter Temperaturen ein besonderes Ereignis.
Bis weitere Informationen zu der Interaktion verfügbar sind, sollten zukünftige Studien zur Kombinationstherapie mit Cisplatin sorgfältig überwacht und Nebenwirkungen eindeutig dokumentiert werden. Dieser Fall deutet darauf hin, dass Umgebungsbedingungen zur Entwicklung der RRD beitragen können. Dieser Fall impliziert auch, dass weder Fraktionsgröße, noch Strahlendosis bestimmende Faktoren bei der Entwicklung der dermatologischen Reaktion sind.
Concomitant chemoradiotherapy has proven to be an important treatment strategy in nasopharyngeal cancer . The concomitant use, however, is often associated with a remarkable increased risk of toxicity. Modern radiotherapy with intensity-modulated radiation therapy (IMRT) reduces the side effects in organs at risk for a large number of cancers. In this technique, radiotherapy is optimized by using a set of optimal stationary and moving beams with varying weights for a desired dose distribution. Despite these efforts, skin toxicity is still a major problem in many entities, especially head and neck cancer.
The radiation recall reaction (RRR) after radiotherapy has been defined as the “recalling” of an effect similar in appearance to that of an acute radiation reaction in a previously irradiated field . The phenomenon is precipitated by the use of a triggering compound after radiation therapy. Radiation recall dermatitis (RRD) is the development of an acute dermatologic reaction in a previously irradiated area of skin after the administration of an aggravating agent days to years after radiotherapy.
To contribute to the knowledge of this phenomenon, we report a case of RRD induced by cold weather in a patient with a nasopharyngeal carcinoma after concurrent chemoradiotherapy.
A 68-year-old Caucasian female patient attended the radiation oncology department at our clinic complaining of a sudden painful swelling and erythema of the head and neck without any fever. The symptoms were noted 3 days earlier. The patient’s medical history included management at our institution for an undifferentiated non-keratinizing invasive squamous cell carcinoma of the nasopharynx classified as T2N2cM0, stage III, according to the 2009 American Joint Committee on Cancer staging system. Initial complaints were ear and neck pain on the right side as well as dysphagia. She had also noticed swelling of the neck lymph nodes. She had lost 8 kg in the last year and at presentation weighed 62 kg without complaints of anorexia. Positron emission tomography (PET)-computed tomography (CT) revealed a hypermetabolic process proceeding from the right lateral and posterior nasopharynx, crossing the midline, and extending to the oropharynx. Several suspect lymph nodes were observed bilaterally in zone IIA and IIB, and anatomopathological examination was performed on tissue obtained by punction of a suspect node on the left side.
This case was discussed in a multidisciplinary team meeting and management of the malignancy included concurrent chemoradiotherapy with curative intentions. The first cycle of chemotherapy started on the same day radiotherapy was initiated, 15 November. Total treatment time was 7 weeks and the last fraction of radiotherapy was administered on 7 January. The patient received 1-week cycles of cisplatinum chemotherapy (according to GFR 3 × 30 mg/m2, 2 × 25 mg/m2, 2 × 20 mg/m2) without the need for hospitalization; the last cycle was administered on 3 January. For radiotherapy, 70 Gy was given to the tumor and affected lymph nodes (CTV + 5 mm margin to PTV) and 50 Gy to the bilateral retropharyngeal, submental, submandibular, upper, middle, and lower internal jugular and spinal accessory lymph nodes (nodes + 3 mm margin to PTV), in daily fractions of 2 Gy using external beam IMRT. IMRT was delivered with a dynamic multileaf collimator system using a sliding-window approach and megavoltage 6-MV beams were used. During treatment, the patient developed mild mucositis (grade II), which was treated symptomatically with mouth washes (based on anti-inflammatory and anti-infectious substances) and pain medication. She had no erythema at the end of treatment (Fig. 1).
At admission on 16 January (9 days after the last fraction of radiotherapy and 13 days after the last cycle of chemotherapy), a head and neck examination revealed no signs of local recurrence or mucositis. The patient had extensive, tender, bilateral erythema and micropapular eruptions at the level of the skin previously radiated. This painful inflammatory erythema was strictly limited to the previously irradiated area. She did not receive any other cytotoxic, hormonal, or antimicrobial pharmacotherapy; nor did she change any soap, detergent, cologne, or skin care product. Extreme cold temperatures were considered to be the causative factor in the absence of any other precipitating agent (Table 1). The patient had been walking outside for about 2 h every day since the end of therapy. Oral methylprednisolone (32 mg) was administered for 1 week, together with ebastine and a local methylprednisolone application. After 7 days, the RRD had disappeared and therefore we gradually stopped administering methylprednisolone.
Daily maximum and minimum temperatures (T)
Daily max T (°C)
Daily min T (°C)
RRRs are inflammatory reactions that occur in previously irradiated areas. The phenomenon is generally triggered by the administration of antineoplastic agents such as chemotherapy or antimetabo-lites, and infrequently by other drugs or physical agents. The most common chemotherapeutic agents implicated with RRR are anthracyclines (doxorubicin and idarubicin) and taxanes (paclitaxel and docetaxel) [9, 10, 13]. Others are cytarabine, bleomycin, capecitabine, vinblastin, etoposide, methotrexate, trimetrexate, edatrexate, melphalan, dacarbazine, oxaliplatin, dactinomycin, hydroxyurea, 5-fluorouracil, gemcitabine, and interferon-alpha. Examples of additional drugs that may elicit the phenomenon are antibiotics such as sulfate, isoniazid, pyrazinamide, tobramycin, ciprofloxacin, and cefazolin, as well as simvastatin, tamoxifen, and targeted therapy [1, 3, 6, 7, 9, 15–17, 19, 21, 22, 24, 25, 27, 31, 35, 39]. One case reports the phenomenon occurring after UV light exposure .
In the vast majority of cases, the RRR involves the skin (approximately 63 %), but internal organs can also be affected [3, 9, 16, 20]. The first case of RRD was reported in 1959 by D’Angio et al., who noticed the reaction following treatment with actinomycin . RRD resembles a severe sunburn at a previously irradiated site. The reaction includes a maculopapular eruption with erythema, edema, vesicle formation, and skin desquamation. The reaction can range in severity from a mild rash to severe necrosis of the skin . Patients commonly report pruritus or pain. By definition, such inflammato-ry reactions occur exclusively in fields of prior irradiation that were quiescent before the “recall.” Skin lesions commonly appear within days to weeks after exposure to the precipitating agent.
The histologic findings of skin biopsies in patients with RRD have been described by Smith et al., and include dermal fibrosis, epidermal dysplasia, keratinocytes with necrosis, increased mitosis, mixed inflammatory infiltrate, and an increase in p53 staining . The underlying physiopathologic mechanism remains poorly understood. Several hypotheses have been proposed. One theory implies radiation-induced alterations of the local vascular permeability that may affect the pharmacokinetics of certain drugs. Others suggest a radiation-induced depletion of epithelial stem cells by heritable mutations, with an impaired ability to proliferate in order to maintain the functional and morphologic integrity of the irradiated tissue, or a greater stem-cell sensitivity to cytotoxic drugs [3, 9]. Seymour et al. suggested that radiation-induced mutations might contribute to this phenomenon in the surviving cell population . Another theory suggests that a memory effect is induced in the surviving cells after radiation, leading to the recall in response to further insults by cytotoxic agents . Studies on the regulation of inflammatory cytokines by irradiation support the last idiosyncratic drug hypersensitivity hypothesis [23, 37]. This hypothesis suggests that radiation can induce nonspe-cific long-lasting secretion of inflammatory mediators in irradiated tissues, such as interleukin-1, interleukin-6, platelet-derived growth factor beta, tumor-necrosis factor alpha, or transforming growth factor beta [3, 9, 41]. When up-regulated by a second agent, these cytokines more readily cause a recall inflammatory reaction. This hypothesis is further supported by the fact that RRD patients typically benefit from treatment with steroids and by the timing of symptom onset, which can be within a few minutes.
Tan et al. presented the only data on the incidence of RRD, in which 47 % of pediatric patients developed RRD triggered by actinomycin D . Zouhair et al. proposed to collect all future radiation recall phenomena in a Rare Cancer Network database in order to augment understanding of this rare reaction .
In the medical literature, the time inter-val between the completion of radiotherapy and RRR vary from minutes to years, but this phenomenon usually occurs with-in months after the end of radiation ther-apy. The radiation doses in reported cases range from 10 to 81 Gy [3, 8, 9, 18]. There is no clear relationship between acute and late skin radiation reactions and the development of RRD [3, 9]. Rather, an interplay between dose and time before the provocative exposure seems to affect both the risk and speed of onset of recall.
While a moderate recall syndrome may resolve spontaneously, the treatment of a more severe RRD, such as in our case, involves the use of corticosteroids (topical, oral or intravenous) or nonsteroidal anti-inflammatory agents [3, 14].
To our knowledge and from a Med-line and PubMed analysis, only ten cases have been reported to date concerning RRR following radiation therapy for head and neck malignancies [5, 11, 13, 14, 20, 26, 29, 38, 40, 44] and only three cases following cisplatin [4, 28, 43].
As in urticaria (hives), we can assume there is an influence of cold on the development of a skin reaction. Treatment includes antihistamines, since the degranulation of mast cells is the etiological cause. Physical urticaria is a subtype of urticaria that, in contrast to the autoimmune, idiopathic, or contact variants, is induced by physical stimuli, such as exercise, temperature, external pressure, sunlight, and water exposure. Cold urticaria develops as aresult of cold exposure with changes in skin temperature. Pruritus and hives may appear when the skin is exposed to temperatures below 4 °C, particularly when conditions are damp and windy. Other cold-induced dermatoses include physiological livedo reticularis, chilblains (pernio), Raynaud phenomenon, cold panniculitis, frostnip, and frostbite .
The recall phenomenon reported here with the use of cisplatin is what we believe to be the first case under such circumstances. Firstly, RRR usually occurs when the patient is given chemothera-py after previous radiotherapy alone. In our patient, 7 weeks of concomitant therapy were uneventful apart from a mild mucositis, which had completely disappeared at the end of treatment. Concomitant therapy was initiated on 15 November and ended on 7 January. The last cycle of cisplatinum weekly was administered on 3 January. The patient presented at our department 9 days after the last fraction of radiotherapy and 13 days after the last cycle of chemotherapy. This may suggest that cisplatin itself, the timing, or the dosage is implicated in the mechanism of the severe RRD. However, we believe the cold weather with freezing temperatures was the major precipitating factor in our case. Another remarkable note in this case is the distribution of the RRD. The phenomenon was distributed over the whole area that was irradiated, not only the boost area that received a higher dose. We defined skin dose as the mean dose to the surface volume (2 mm thickness) in the irradiated region. The mean skin dose was 20 Gy, the maximum skin dose was 63.7 Gy. This suggests that the development of RRD might be independent of either fraction size or total dose in contrast to what has been proposed in the literature .
RRR is a rare but well-described phenomenon, without clear radiation or drug-specific characteristics. In the medical literature, radiation recall following cold exposure seems to be an exceptional event. The etiology remains unknown, but is probably due to an idiosyncratic drug hypersensitivity reaction, in which a second agent can recall the inflammatory reaction. Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction.
Compliance with ethical guidelines
Conflict of interest
I. Kindts, K. Stellamans, M. Bonny, N. Planckaert, and L. Goethals state that there are no conflicts of interest.