Case study Strahlenther Onkol 2014 DOI 10.1007/s00066-014-0632-2 Received: 16 October 2013 Accepted: 22 January 2014
Isabelle Kindts1 · Karin Stellamans1 · Michiel Bonny2 · Nikie Planckaert1 · Laurence Goethals1 1Department of Radiation Oncology, AZ Groeninge Hospital, Kortrijk, Belgium 2Department of Dermatology, AZ Groeninge Hospital, Kortrijk, Belgium
© Springer-Verlag Berlin Heidelberg 2014
Case report of cold-weatherinduced radiation recall dermatitis after chemoradiotherapy with cisplatin Concomitant chemoradiotherapy has proven to be an important treatment strategy in nasopharyngeal cancer [2]. 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 [3]. 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.
Case report 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 previStrahlentherapie und Onkologie X · 2014
| 1
Case study
Fig. 1 9 Posterior (a) and anterior (b) view of the radiation recall dermatitis. Anterior (c) and lateral (d) dose distribution
ously 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.
Discussion 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 antimetabolites, 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 cytara-
2 | Strahlentherapie und Onkologie X · 2014
bine, 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 [26]. 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 [12]. RRD resembles a severe sunburn at a previously irradiated site. The reaction includes a maculopap ular 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 [33]. Patients commonly report pruritus or pain. By definition, such inflammatory 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 [32]. 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 [30]. Another theory suggests that a memory effect is induced in the surviving cells after radiation, leading to the recall in response
Abstract · Zusammenfassung to further insults by cytotoxic agents [42]. 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 nonspecific long-lasting secretion of inflamma tory mediators in irradiated tissues, such as interleukin-1, interleukin-6, plateletderived 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 [34]. 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 [3]. In the medical literature, the time interval between the completion of radiotherapy and RRR vary from minutes to years, but this phenomenon usually occurs within months after the end of radiation therapy. 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 antiinflammatory agents [3, 14]. To our knowledge and from a Medline 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 in-
Strahlenther Onkol 2014 DOI 10.1007/s00066-014-0632-2 © Springer-Verlag Berlin Heidelberg 2014 I. Kindts · K. Stellamans · M. Bonny · N. Planckaert · L. Goethals
Case report of cold-weather-induced radiation recall dermatitis after chemoradiotherapy with cisplatin Abstract Background. 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. Case report. 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.
Conclusion. 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. Keywords Recall dermatitis · Chemoradiation · Cisplatin · Head and neck cancer · Cold temperature
Fallbericht einer kaltwetterinduzierten „Radiation-Recall“Dermatitis nach einer Radiochemotherapie mit Cisplatin Zusammenfassung Hintergrund. 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. Fallbericht. 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.
cludes 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 a result 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
Schlussfolgerung. 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. Schlüsselwörter Recall-Dermatitis · Radiochemotherapie · Cisplatin · Kopf-Hals-Tumor · Kalte Temperatur
conditions are damp and windy. Other cold-induced dermatoses include physi ological livedo reticularis, chilblains (pernio), Raynaud phenomenon, cold panniculitis, frostnip, and frostbite [36]. 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 chemotherapy after previous radiotherapy alone. In our patient, 7 weeks of concomitant therStrahlentherapie und Onkologie X · 2014
| 3
Case study Table 1 Daily maximum and minimum
temperatures (T) Date 7/01/2013 8/01/2013 9/01/2013 10/01/2013 11/01/2013 12/01/2013 13/01/2013 14/01/2013 15/01/2013 16/01/2013
Daily max T (°C) 8 7 7 6 3 2 0 0 0 − 1
Daily min T (°C) 6 6 4 3 − 1 − 2 − 3 − 5 − 6 − 10
apy 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 [28].
Conclusion RRR is a rare but well-described phenomenon, without clear radiation or drugspecific 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
4 | Strahlentherapie und Onkologie X · 2014
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.
Corresponding address I. Kindts Department of Radiation Oncology AZ Groeninge Hospital Loofstraat 43, 8500 Kortrijk [email protected] [email protected]
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.
References 1. Abadir R, Liebmann J (1995) Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol 7:325–326 2. Al-Sarraf M, LeBlanc M, Giri PG et al (1998) Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310–1317 3. Azria D, Magné N, Zouhair A et al (2005) Radiation recall: a well recognized but neglected phenomenon. Cancer Treat Rev 31:555–570 4. Baek SW, Seo YJ, Kim JS, Lee HJ (2012) Radiation recall dermatitis after treatment with Paclitaxel and Cisplatin. Ann Dermatol 24:223–224 5. Beddis IR, Mott MG, Bullimore J (1983) Case resport: nasopharyngeal rhabdomyosarcoma and Gorlin’s naevoid basal cell carcinoma syndrome. Med Pediatr oncol 11:178–179 6. Bokemeyer C, Lampe C, Heneka M, Schabet M, Bamberg M, Kanz L (1996) Paclitaxel-induced radiation recall dermatitis. Ann of Oncol 7:755–756 7. Burdon J, Bell R, Sullivan J, Henderson M (1978) Adriamycin-induced recall phenomenon 15 years after radiotherapy. JAMA 239:931 8. Caloglu M, Yurut-Caloglu V, Cosar-Alas R, Saynak M, Karagol H, Uzal C (2007) An ambiguous phenomenon of radiation and drugs: recall reactions. Onkologie 30:209–214 9. Camidge R, Price A (2001) Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 59:237–245
10. Cassady JR, Richter MP, Piro AJ, Jaffe N (1975) Radiation-adriamycin interactions. Preliminary clinical observations. Cancer 36:946–949 11. Culp LR, Pou AM, Jones DV, Bayouth J, Sanguineti G (2004) A case of radiation recall mucositis associated with docetaxel. Head Neck 26:197–200 12. D’Angio GJ, Farber S, Maddock CL (1959) Potentiation of x-ray effects by actinomycin D. Radiology 73:175–177 13. Donaldson SS, Glick JM, Wilbur JR (1974) Letter: Adriamycin activating a recall phenomenon after radiation therapy. Ann Intern Med 81:407–408 14. Eifel PJ, McClure S (1989) Severe chemotherapyinduced recall of radiation mucositis in a patient with non-Hodgkin’s lymphoma of Waldeyer’s ring. Int J Radiat Oncol Biol Phys 17:907–908 15. Extermann M, Vogt N, Forni M, Dayer P (1995) Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol 48:77–78 16. Friedlander PA, Bansal R, Schwartz L, Wagman R, Posner J, Kemeny N (2004) Gemcitabine-related radiation recall preferentially involves internal tissue and organs. Cancer 100:1793–1799 17. Haas RL, de Klerk G (2011) An illustrated case of doxorubicin-induced radiation recall dermatitis and a review of the literature. Neth J Med 69:72– 75 18. Hird AE, Wilson J, Symons S, Sinclair E, Davis M, Chow E (2008) Radiation recall dermatitis: case report and review of the literature. Curr Oncol 15:53–62 19. Hureaux J, Le Guen Y, Tuchais C, Savary L, Urban T (2005) Radiation recall dermatitis with pemetrexed. Lung Cancer 50:255–258 20. Indinnimeo M, Cicchini C, Kanakaki S, Larcinese A, Mingazzini PL (2003) Chemotherapy-induced radiation recall myositis. Oncol Rep 10:1401–1403 21. Jain S, Agarwal J, Laskar S, Gupta T, Shrivastava S (2008) Radiation recall dermatitis with gatifloxacin: a review of literature. J Med Imaging Radiat Oncol 52:191–193 22. Jeter MD, Jänne PA, Brooks S et al (2002) Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys 53:394–400 23. Johnston C, Piedboeuf B, Rubin P, Williams JP, Baggs R, Finkelstein JN (1996) Early and persistent alterations in the expression of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor alpha mRNA levels in fibrosis-resistant and sensitive mice after thoracic irradiation. Radiat Res 145:762– 767 24. Kandemir EG, Karabudak O, Maydagli A (2005) Docetaxel-induced radiation recall dermatitis. Swiss Med Wkly 135:34–35 25. Kang SK (2006) Images in clinical medicine. Radiation recall reaction after antimicrobial therapy. N Engl J Med 354:622 26. Le Scodan R, Wyplosz B, Couchon S, Housset M, Laccourreye O (2007) UV-light induced radiation recall dermatitis after a chemoradiotherapy organ preservation protocol. Eur Arch Otorhinolaryngol 264:1099–1102 27. Levy A, Hollebecque A, Bourgier C et al (2013) Targeted therapy-induced radiation recall. Eur J Cancer 49:1662–1668 28. Melnyk SM, More KF, Miles EF (2012) Idiopathic radiation recall dermatitis developing nine months after cessation of cisplatin therapy in treatment of squamous cell carcinoma of the tonsil. Case Rep Oncol Med 2012:271801 29. Putnik K, Stadler P, Schäfer C, Koelbl O (2006) Enhanced radiation sensitivity and radiation recall dermatitis (RRD) after hypericin therapy – case report and review of literature. Radiat Oncol 1:32
30. Seymour C, Mothersill Q, Alper T (1986) High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Phys 50:167–179 31. Singer EA, Warren RD, Pennanen MF, Collins BT, Hayes DF (2004) Tamoxifen-induced radiation recall dermatitis. Breast J 10:170–171 32. Smith KJ, Germain M, Skelton H et al (2002) Histopathologic features seen with radiation recall or enhancement eruptions. J Cutan Med Surg 6:535– 540 33. Susser WS, Whitaker-Worth DL, Grant-Kels JM (1999) Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 40:367–398 34. Tan CT, Dargeon HW, Bruchenal JH (1959) The effect of actinomycin D on cancer in childhood. Pediatrics 24:544–561 35. Thomas R, Stea B (2002) Radiation recall dermatitis from high-dose interferon alfa-2b. J Clin Oncol 20:355–357 36. Tlougan BE, Mancini AJ, Mandell JA, Cohen DE, Sanchez MR (2011) Skin conditions in figure skaters, ice-hockey players and speed skaters: part II— cold-induced, infectuous and inflammatory dermatoses. Sports Med 41:967–984 37. Vozenin-Brotons MC, Gault N, Sivan V et al (1999) Histopathological and cellular studies of a case of cutaneous radiation syndrome after accidental chronic exposure to a cesium source. Radiat Res 152:332–337 38. Wallenborn PA 3rd, Postma DS (1984) Radiation recall supraglottis. A hazard in head and neck chemotherapy. Arch Otolaryngol 110:614–617 39. Wernicke AG, Swistel AJ, Prashar B, Myskowski PL (2010) Levofloxacin-induced radiation recall dermatitis: a case report and a review of the literature. Clin Breast Cancer 10:404–406 40. Wiatrak BJ, Myers CM 3rd (1991) Radiation recall supraglottis in a child. Am J Orolaryngol 12:227– 229 41. Wintroub BU, Stern R (1985) Cutaneous drug reactions: pathogenesis and clinical classification. J Am Acad Dermatol 13:167–179 42. Yeo W, Johnson PJ (2000) Radiation-recall skin disorders associated with the use of antineoplastic drugs: pathogenesis, prevalence and management. Am J Clin Dermatol 1:113–116 43. Zhu ZF, Fan M, Fu XL (2010) Radiation recall with vinorelbine and cisplatin. Onkologie 33:107–109 44. Zulian GB, Aapro MS (1994) Docetaxel and radiation-recall severe mucositis. Ann Oncol 5:964
Strahlentherapie und Onkologie X · 2014
| 5
Isabelle Kindts1 · Karin Stellamans1 · Michiel Bonny2 · Nikie Planckaert1 · Laurence Goethals1 1Department of Radiation Oncology, AZ Groeninge Hospital, Kortrijk, Belgium 2Department of Dermatology, AZ Groeninge Hospital, Kortrijk, Belgium
© Springer-Verlag Berlin Heidelberg 2014
Case report of cold-weatherinduced radiation recall dermatitis after chemoradiotherapy with cisplatin Concomitant chemoradiotherapy has proven to be an important treatment strategy in nasopharyngeal cancer [2]. 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 [3]. 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.
Case report 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 previStrahlentherapie und Onkologie X · 2014
| 1
Case study
Fig. 1 9 Posterior (a) and anterior (b) view of the radiation recall dermatitis. Anterior (c) and lateral (d) dose distribution
ously 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.
Discussion 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 antimetabolites, 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 cytara-
2 | Strahlentherapie und Onkologie X · 2014
bine, 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 [26]. 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 [12]. RRD resembles a severe sunburn at a previously irradiated site. The reaction includes a maculopap ular 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 [33]. Patients commonly report pruritus or pain. By definition, such inflammatory 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 [32]. 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 [30]. Another theory suggests that a memory effect is induced in the surviving cells after radiation, leading to the recall in response
Abstract · Zusammenfassung to further insults by cytotoxic agents [42]. 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 nonspecific long-lasting secretion of inflamma tory mediators in irradiated tissues, such as interleukin-1, interleukin-6, plateletderived 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 [34]. 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 [3]. In the medical literature, the time interval between the completion of radiotherapy and RRR vary from minutes to years, but this phenomenon usually occurs within months after the end of radiation therapy. 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 antiinflammatory agents [3, 14]. To our knowledge and from a Medline 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 in-
Strahlenther Onkol 2014 DOI 10.1007/s00066-014-0632-2 © Springer-Verlag Berlin Heidelberg 2014 I. Kindts · K. Stellamans · M. Bonny · N. Planckaert · L. Goethals
Case report of cold-weather-induced radiation recall dermatitis after chemoradiotherapy with cisplatin Abstract Background. 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. Case report. 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.
Conclusion. 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. Keywords Recall dermatitis · Chemoradiation · Cisplatin · Head and neck cancer · Cold temperature
Fallbericht einer kaltwetterinduzierten „Radiation-Recall“Dermatitis nach einer Radiochemotherapie mit Cisplatin Zusammenfassung Hintergrund. 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. Fallbericht. 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.
cludes 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 a result 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
Schlussfolgerung. 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. Schlüsselwörter Recall-Dermatitis · Radiochemotherapie · Cisplatin · Kopf-Hals-Tumor · Kalte Temperatur
conditions are damp and windy. Other cold-induced dermatoses include physi ological livedo reticularis, chilblains (pernio), Raynaud phenomenon, cold panniculitis, frostnip, and frostbite [36]. 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 chemotherapy after previous radiotherapy alone. In our patient, 7 weeks of concomitant therStrahlentherapie und Onkologie X · 2014
| 3
Case study Table 1 Daily maximum and minimum
temperatures (T) Date 7/01/2013 8/01/2013 9/01/2013 10/01/2013 11/01/2013 12/01/2013 13/01/2013 14/01/2013 15/01/2013 16/01/2013
Daily max T (°C) 8 7 7 6 3 2 0 0 0 − 1
Daily min T (°C) 6 6 4 3 − 1 − 2 − 3 − 5 − 6 − 10
apy 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 [28].
Conclusion RRR is a rare but well-described phenomenon, without clear radiation or drugspecific 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
4 | Strahlentherapie und Onkologie X · 2014
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.
Corresponding address I. Kindts Department of Radiation Oncology AZ Groeninge Hospital Loofstraat 43, 8500 Kortrijk [email protected] [email protected]
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.
References 1. Abadir R, Liebmann J (1995) Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol 7:325–326 2. Al-Sarraf M, LeBlanc M, Giri PG et al (1998) Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310–1317 3. Azria D, Magné N, Zouhair A et al (2005) Radiation recall: a well recognized but neglected phenomenon. Cancer Treat Rev 31:555–570 4. Baek SW, Seo YJ, Kim JS, Lee HJ (2012) Radiation recall dermatitis after treatment with Paclitaxel and Cisplatin. Ann Dermatol 24:223–224 5. Beddis IR, Mott MG, Bullimore J (1983) Case resport: nasopharyngeal rhabdomyosarcoma and Gorlin’s naevoid basal cell carcinoma syndrome. Med Pediatr oncol 11:178–179 6. Bokemeyer C, Lampe C, Heneka M, Schabet M, Bamberg M, Kanz L (1996) Paclitaxel-induced radiation recall dermatitis. Ann of Oncol 7:755–756 7. Burdon J, Bell R, Sullivan J, Henderson M (1978) Adriamycin-induced recall phenomenon 15 years after radiotherapy. JAMA 239:931 8. Caloglu M, Yurut-Caloglu V, Cosar-Alas R, Saynak M, Karagol H, Uzal C (2007) An ambiguous phenomenon of radiation and drugs: recall reactions. Onkologie 30:209–214 9. Camidge R, Price A (2001) Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 59:237–245
10. Cassady JR, Richter MP, Piro AJ, Jaffe N (1975) Radiation-adriamycin interactions. Preliminary clinical observations. Cancer 36:946–949 11. Culp LR, Pou AM, Jones DV, Bayouth J, Sanguineti G (2004) A case of radiation recall mucositis associated with docetaxel. Head Neck 26:197–200 12. D’Angio GJ, Farber S, Maddock CL (1959) Potentiation of x-ray effects by actinomycin D. Radiology 73:175–177 13. Donaldson SS, Glick JM, Wilbur JR (1974) Letter: Adriamycin activating a recall phenomenon after radiation therapy. Ann Intern Med 81:407–408 14. Eifel PJ, McClure S (1989) Severe chemotherapyinduced recall of radiation mucositis in a patient with non-Hodgkin’s lymphoma of Waldeyer’s ring. Int J Radiat Oncol Biol Phys 17:907–908 15. Extermann M, Vogt N, Forni M, Dayer P (1995) Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol 48:77–78 16. Friedlander PA, Bansal R, Schwartz L, Wagman R, Posner J, Kemeny N (2004) Gemcitabine-related radiation recall preferentially involves internal tissue and organs. Cancer 100:1793–1799 17. Haas RL, de Klerk G (2011) An illustrated case of doxorubicin-induced radiation recall dermatitis and a review of the literature. Neth J Med 69:72– 75 18. Hird AE, Wilson J, Symons S, Sinclair E, Davis M, Chow E (2008) Radiation recall dermatitis: case report and review of the literature. Curr Oncol 15:53–62 19. Hureaux J, Le Guen Y, Tuchais C, Savary L, Urban T (2005) Radiation recall dermatitis with pemetrexed. Lung Cancer 50:255–258 20. Indinnimeo M, Cicchini C, Kanakaki S, Larcinese A, Mingazzini PL (2003) Chemotherapy-induced radiation recall myositis. Oncol Rep 10:1401–1403 21. Jain S, Agarwal J, Laskar S, Gupta T, Shrivastava S (2008) Radiation recall dermatitis with gatifloxacin: a review of literature. J Med Imaging Radiat Oncol 52:191–193 22. Jeter MD, Jänne PA, Brooks S et al (2002) Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys 53:394–400 23. Johnston C, Piedboeuf B, Rubin P, Williams JP, Baggs R, Finkelstein JN (1996) Early and persistent alterations in the expression of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor alpha mRNA levels in fibrosis-resistant and sensitive mice after thoracic irradiation. Radiat Res 145:762– 767 24. Kandemir EG, Karabudak O, Maydagli A (2005) Docetaxel-induced radiation recall dermatitis. Swiss Med Wkly 135:34–35 25. Kang SK (2006) Images in clinical medicine. Radiation recall reaction after antimicrobial therapy. N Engl J Med 354:622 26. Le Scodan R, Wyplosz B, Couchon S, Housset M, Laccourreye O (2007) UV-light induced radiation recall dermatitis after a chemoradiotherapy organ preservation protocol. Eur Arch Otorhinolaryngol 264:1099–1102 27. Levy A, Hollebecque A, Bourgier C et al (2013) Targeted therapy-induced radiation recall. Eur J Cancer 49:1662–1668 28. Melnyk SM, More KF, Miles EF (2012) Idiopathic radiation recall dermatitis developing nine months after cessation of cisplatin therapy in treatment of squamous cell carcinoma of the tonsil. Case Rep Oncol Med 2012:271801 29. Putnik K, Stadler P, Schäfer C, Koelbl O (2006) Enhanced radiation sensitivity and radiation recall dermatitis (RRD) after hypericin therapy – case report and review of literature. Radiat Oncol 1:32
30. Seymour C, Mothersill Q, Alper T (1986) High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Phys 50:167–179 31. Singer EA, Warren RD, Pennanen MF, Collins BT, Hayes DF (2004) Tamoxifen-induced radiation recall dermatitis. Breast J 10:170–171 32. Smith KJ, Germain M, Skelton H et al (2002) Histopathologic features seen with radiation recall or enhancement eruptions. J Cutan Med Surg 6:535– 540 33. Susser WS, Whitaker-Worth DL, Grant-Kels JM (1999) Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 40:367–398 34. Tan CT, Dargeon HW, Bruchenal JH (1959) The effect of actinomycin D on cancer in childhood. Pediatrics 24:544–561 35. Thomas R, Stea B (2002) Radiation recall dermatitis from high-dose interferon alfa-2b. J Clin Oncol 20:355–357 36. Tlougan BE, Mancini AJ, Mandell JA, Cohen DE, Sanchez MR (2011) Skin conditions in figure skaters, ice-hockey players and speed skaters: part II— cold-induced, infectuous and inflammatory dermatoses. Sports Med 41:967–984 37. Vozenin-Brotons MC, Gault N, Sivan V et al (1999) Histopathological and cellular studies of a case of cutaneous radiation syndrome after accidental chronic exposure to a cesium source. Radiat Res 152:332–337 38. Wallenborn PA 3rd, Postma DS (1984) Radiation recall supraglottis. A hazard in head and neck chemotherapy. Arch Otolaryngol 110:614–617 39. Wernicke AG, Swistel AJ, Prashar B, Myskowski PL (2010) Levofloxacin-induced radiation recall dermatitis: a case report and a review of the literature. Clin Breast Cancer 10:404–406 40. Wiatrak BJ, Myers CM 3rd (1991) Radiation recall supraglottis in a child. Am J Orolaryngol 12:227– 229 41. Wintroub BU, Stern R (1985) Cutaneous drug reactions: pathogenesis and clinical classification. J Am Acad Dermatol 13:167–179 42. Yeo W, Johnson PJ (2000) Radiation-recall skin disorders associated with the use of antineoplastic drugs: pathogenesis, prevalence and management. Am J Clin Dermatol 1:113–116 43. Zhu ZF, Fan M, Fu XL (2010) Radiation recall with vinorelbine and cisplatin. Onkologie 33:107–109 44. Zulian GB, Aapro MS (1994) Docetaxel and radiation-recall severe mucositis. Ann Oncol 5:964
Strahlentherapie und Onkologie X · 2014
| 5
