Practical Radiation Oncology (2015) 5, 263-266
www.practicalradonc.org
Teaching Case
Radiation recall precipitated by iodinated nonionic contrast Steven K.M. Lau MD, PhD, Asal Rahimi MD, MS ⁎ Department of Radiation Oncology, University of Texas Southwestern, Dallas, Texas Received 22 October 2014; revised 4 November 2014; accepted 7 November 2014
Introduction Radiation recall is a rare, poorly understood clinical syndrome characterized by an acute inflammatory reaction in the distribution of prior radiation exposure. It is most commonly precipitated by chemotherapy, but noncytotoxic medications have also been described as triggering agents. 1,2 Radiation recall most commonly presents as dermatitis (RRD) involving the skin but can manifest in deep tissues, including critical structures. 3 Herein, we report a case of RRD precipitated by nonionic contrast.
Case presentation A 63-year-old asthmatic woman allergic to iodinated intravenous contrast (hives), penicillins, and sulfa drugs was diagnosed with hormone-positive stage III carcinoma of the right breast in December 2011. Using a standard premedication regimen for her contrast allergy (Table 1), staging computed tomography (CT) of the neck, chest, abdomen, and pelvis with intravenous contrast was performed without event. She completed neoadjuvant chemotherapy with dose-dense doxorubicin, cyclophosphamide, and paclitaxel and subsequently underwent bilateral skin-sparing mastectomy with expander placement.
Conflicts of interest: None. ⁎ Corresponding author. University of Texas Southwestern, Moncrief Radiation Oncology Center, 5801 Forest Park Rd, Dallas, TX 75390-9183. E-mail address: [email protected] (A. Rahimi).
She completed postmastectomy radiation with curative intent using a standard 3-field monoisocentric technique in September 2012. The chest wall and supraclavicular area received 5040 cGy in 28 fractions, followed by a 1000-cGy boost to the mastectomy scar in 5 fractions. Treatment was well tolerated, with brisk erythema in the treatment fields and desquamation in the right axillary fold and lateral chest wall (Fig 1). These areas healed within 4 weeks. She began anastrozole 3 weeks after radiation therapy. Seven weeks after radiation therapy, she underwent CT of the abdomen with iodine-based nonionic contrast for surveillance of a 6-mm hepatic hemangioma. She was premedicated using the standard regimen previously used and adequate for her contrast allergy. Several hours after the study, she developed brisk, well-demarcated erythema of the chest wall and supraclavicular area in the distribution of her radiation portals. Dermatitis persisted with constant intensity for 3 days and then subsided without intervention. No desquamation, pain, or tenderness occurred. She continued anastrozole during this time and had not taken any new medications. Therefore, her RRD was suspected to have been precipitated by nonionic contrast. She was instructed to escalate her anti-inflammatory regimen before and after future exposure to intravenous contrast (Table 1). Eighteen weeks after radiation therapy, she underwent CT of the head with intravenous contrast for headaches. Despite increased premedication, she again developed dermatitis that mirrored her radiation portals (Fig 2). The severity of reaction was attenuated compared with the initial episode. Again, no new medications were identified, and her anti-inflammatory regimen was increased (Table 1). Two years after radiation therapy, she underwent CT of the neck and chest with intravenous contrast for neck
http://dx.doi.org/10.1016/j.prro.2014.11.002 1879-8500/Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.
264 Table 1
S.K.M. Lau, A. Rahimi
Practical Radiation Oncology: July-August 2015
Anti-inflammatory regimen for preexisting iodine-based contrast allergy and RRD
Before RRD
After first RRD event
After second RRD event
Premedication
Postmedication
Prednisone 50 mg at 13, 7, and 1 h before CT scan Diphenhydramine 25 mg 1 h before CT scan Prednisone 50 mg at 13, 7, and 1 h before CT scan Diphenhydramine 50 mg at 13, 7, and 1 h before CT scan
None
Prednisone 75 mg at 13, 7, and 1 h before CT scan Diphenhydramine 50 mg at 13, 7, and 1 h before CT scan
Prednisone 50 mg at 12, 18, 24, and 30 h after CT scan, and 25 mg at 36, 42, 48, and 54 h after CT scan Diphenhydramine 50 mg every 12 h after CT scan until prednisone completed Prednisone 75 mg at 12, 18, 24, and 30 h after CT scan, and 25 mg at 36, 42, 48, and 54 h after CT scan Diphenhydramine 50 mg every 12 h after CT scan until prednisone completed
CT, computed tomography; RRD, radiation recall dermatitis.
swelling. Despite higher premedication doses, she again developed RRD; however, the intensity was markedly decreased. She remained compliant with anastrozole and denied having taken new medications.
Discussion RRD is rare and characterized by sharply defined borders that correlate to prior radiation fields. Similarly, radiation recall involving deep tissues arises in prior treatment fields. 2,3 To reduce confounding factors, RRD has been defined as occurring (1) more than 7 days after radiotherapy and (2) after complete recovery of acute radiation toxicity. 1 Here, we present a case of RRD precipitated by nonionic contrast in a patient with preexisting sensitivity to iodine-based contrast. The unique circumstances of this case provide new insight into this poorly understood syndrome. Radiation recall is commonly associated with chemotherapeutic agents and recently has been described with targeted therapies, endocrine therapy, antibiotic drugs, and
Figure 1
statins (Table 2). This patient experienced RRD 3 times in the absence of new medications, each time associated with administration of nonionic contrast. Notably, anastrozole was recently associated with RRD. 4 This patient was compliant with daily anastrozole leading up to, during, and after each consecutive event. Therefore, RRD was likely related to the imaging study rather than anastrozole. CT scan radiation has not been linked to RRD, but there are 2 reports of RRD attributed to extensive sunlight exposure. 5,6 Moreover, there is 1 case of recall dermatitis after CT scan with contrast in the distribution of laser hair removal that occurred 3 days prior. 7 In the current case, each CT scan was performed with nonionic contrast, and it is difficult to discern whether RRD was precipitated by CT radiation itself or intravenous contrast; however, given an allergy to iodinated contrast, we favor this as the triggering agent. Taken together, RRD can be precipitated by a variety of agents, including nontherapeutic agents. RRD has been reported to recur at attenuated, similar, or worsened intensity with rechallenge, or it may not recur at all. 1,2 Moreover, RRD may subside spontaneously with
Acute radiation dermatitis. A, Pretreatment skin tone; B, dermatitis while on treatment; C, treatment plan skin rendering.
Practical Radiation Oncology: July-August 2015
Figure 2 Second episode of recall dermatitis 18 weeks after radiation.
continuation of the precipitating medications. 8 RRD is typically managed by withdrawal of the offending agent and pulse corticosteroids, although there is minimal evidence to support this practice. Although rechallenge resulted in serial attenuation in this case, it remains unclear whether this was secondary to escalated premedication. Nonetheless, we plan to continue the escalated anti-inflammatory regimen for this patient during future exposures to iodinated contrast. Another consideration for patients with radiation recall reactions limited to the skin is the use of topical corticosteroids or diphenhydramine, which has been described with promising results in recent cases. 9
Table 2
Medications associated with radiation recall
Cancer therapies Alkylating agents Anthracyclines Antimetabolite agents Antifolate agents Aromatase inhibitors Histone deacetylase inhibitors Kinase inhibitors Microtubule stabilizers Monoclonal antibodies mTOR inhibitors Nucleosides Platinum-based agents Selective estrogen receptor modulators Somatostatin analogs Topoisomerase inhibitors Vinca alkaloids Other Amphetamines Antibiotic agents Calcium channel blockers Herbal supplements NSAIDs Statins mTOR, mammalian target of rapamycin; NSAIDS, nonsteroidal anti-inflammatory agents.
Radiation recall
265
The pathogenesis of radiation recall is unknown, and there is no reliable method of identifying patients at risk. Several proposed mechanisms include activation of inflammatory pathways, vascular damage, and progenitor cell depletion or sensitization. 1 Hypothesis validation is difficult because of the rarity and unpredictability of radiation recall. Histologic analysis of RRD has demonstrated nonspecific inflammatory infiltrate. 7,10,11 In this patient with preexisting allergy to iodine-based contrast, RRD was likely precipitated by nonionic contrast. One explanation of this observation is that radiation predisposes local tissues to delayed-type hypersensitivity reactions through currently unidentified mechanisms, possibly by altering the cellular composition. Given their variable presentation, radiation recall syndromes may be composed of a heterogeneous group with similar presentations caused by distinct mechanisms. Reactions to iodinated radiocontrast can be acute or delayed and are thought to be caused by idiosyncratic or T-cell–mediated hypersensitivity reactions, respectively. 12 Risk factors for adverse reactions include history of prior reactions to radiocontrast, asthma, and atopy, all of which this patient had. 12 Monomeric nonionic contrast (as used at our institution) has the lowest risk of adverse reaction, whereas dimeric nonionic contrast has the highest risk. 13 Although prophylactic corticosteroids are commonly used once sensitivity is identified, breakthrough reactions can still occur. Thus, many similarities exist between RRD and hypersensitivity to iodinated contrast, and it is likely they share a common mechanism. In this patient, radiation exposure localized a previously generalized reaction, which suggests radiation-induced sensitization of the local tissue that predisposed it to future events. To the best of our knowledge, this is the first report both of RRD caused by iodinated contrast and of RRD precipitated by a prior allergen despite high-dose premedication. These unique circumstances are suggestive of a radiation-related, delayed-type hypersensitivity reaction. However, the underlying molecular mechanisms of RRD and its optimal management remain unknown.
References 1. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol. 2001;59:237-245. 2. Azria D, Magné N, Zouhair A, et al. Radiation recall: A well recognized but neglected phenomenon. Cancer Treat Rev. 2005;31:555-570. 3. Jeter MD, Jänne PA, Brooks S, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53:394-400. 4. Haydaroglu A, Sert F, Kazandi AC, Unal I. Radiation recall reaction with anastrozole treatment in breast cancer. Pract Radiat Oncol. 2012;2:e65-e68. 5. Del Guidice SM, Gerstley JK. Sunlight-induced radiation recall. Int J Dermatol. 1988;27:415-416. 6. Le Scodan R, Wyplosz B, Couchon S, Housset M, Laccourreye O. UV-light induced radiation recall dermatitis after a chemoradiotherapy organ preservation protocol. Eur Arch Otorhinolaryngol. 2007;264: 1099-1102.
266
S.K.M. Lau, A. Rahimi
7. Córdoba S, Tardío JC, Utrera M, Martínez-Morán C, Borbujo J. Laser recall dermatitis. JAMA Dermatol. 2014;150:212-213. 8. Extermann M, Vogt N, Forni M, Dayer P. Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol. 1995;48:77-78. 9. Boussemart L, Boivin C, Claveau J, et al. Vemurafenib and radiosensitization. JAMA Dermatol. 2013;149:855-857. 10. Boström A, Sjölin-Forsberg G, Wilking N, Bergh J. Radiation recall: Another call with tamoxifen. Acta Oncol. 1999;38:955-959.
Practical Radiation Oncology: July-August 2015 11. Castellano D, Hitt R, Cortés-Funes H, Romero A, Rodriguez-Peralto JL. Side effects of chemotherapy: Case 2: Radiation recall reaction induced by gemcitabine. J Clin Oncol. 2000;18:695-696. 12. Pasternak JJ, Williamson EE. Clinical pharmacology, uses, and adverse reactions of iodinated contrast agents: A primer for the non-radiologist. Mayo Clin Proc. 2012;87:390-402. 13. Sutton AG, Finn P, Grech ED, et al. Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization. Am Heart J. 2001;141:677-683.
www.practicalradonc.org
Teaching Case
Radiation recall precipitated by iodinated nonionic contrast Steven K.M. Lau MD, PhD, Asal Rahimi MD, MS ⁎ Department of Radiation Oncology, University of Texas Southwestern, Dallas, Texas Received 22 October 2014; revised 4 November 2014; accepted 7 November 2014
Introduction Radiation recall is a rare, poorly understood clinical syndrome characterized by an acute inflammatory reaction in the distribution of prior radiation exposure. It is most commonly precipitated by chemotherapy, but noncytotoxic medications have also been described as triggering agents. 1,2 Radiation recall most commonly presents as dermatitis (RRD) involving the skin but can manifest in deep tissues, including critical structures. 3 Herein, we report a case of RRD precipitated by nonionic contrast.
Case presentation A 63-year-old asthmatic woman allergic to iodinated intravenous contrast (hives), penicillins, and sulfa drugs was diagnosed with hormone-positive stage III carcinoma of the right breast in December 2011. Using a standard premedication regimen for her contrast allergy (Table 1), staging computed tomography (CT) of the neck, chest, abdomen, and pelvis with intravenous contrast was performed without event. She completed neoadjuvant chemotherapy with dose-dense doxorubicin, cyclophosphamide, and paclitaxel and subsequently underwent bilateral skin-sparing mastectomy with expander placement.
Conflicts of interest: None. ⁎ Corresponding author. University of Texas Southwestern, Moncrief Radiation Oncology Center, 5801 Forest Park Rd, Dallas, TX 75390-9183. E-mail address: [email protected] (A. Rahimi).
She completed postmastectomy radiation with curative intent using a standard 3-field monoisocentric technique in September 2012. The chest wall and supraclavicular area received 5040 cGy in 28 fractions, followed by a 1000-cGy boost to the mastectomy scar in 5 fractions. Treatment was well tolerated, with brisk erythema in the treatment fields and desquamation in the right axillary fold and lateral chest wall (Fig 1). These areas healed within 4 weeks. She began anastrozole 3 weeks after radiation therapy. Seven weeks after radiation therapy, she underwent CT of the abdomen with iodine-based nonionic contrast for surveillance of a 6-mm hepatic hemangioma. She was premedicated using the standard regimen previously used and adequate for her contrast allergy. Several hours after the study, she developed brisk, well-demarcated erythema of the chest wall and supraclavicular area in the distribution of her radiation portals. Dermatitis persisted with constant intensity for 3 days and then subsided without intervention. No desquamation, pain, or tenderness occurred. She continued anastrozole during this time and had not taken any new medications. Therefore, her RRD was suspected to have been precipitated by nonionic contrast. She was instructed to escalate her anti-inflammatory regimen before and after future exposure to intravenous contrast (Table 1). Eighteen weeks after radiation therapy, she underwent CT of the head with intravenous contrast for headaches. Despite increased premedication, she again developed dermatitis that mirrored her radiation portals (Fig 2). The severity of reaction was attenuated compared with the initial episode. Again, no new medications were identified, and her anti-inflammatory regimen was increased (Table 1). Two years after radiation therapy, she underwent CT of the neck and chest with intravenous contrast for neck
http://dx.doi.org/10.1016/j.prro.2014.11.002 1879-8500/Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.
264 Table 1
S.K.M. Lau, A. Rahimi
Practical Radiation Oncology: July-August 2015
Anti-inflammatory regimen for preexisting iodine-based contrast allergy and RRD
Before RRD
After first RRD event
After second RRD event
Premedication
Postmedication
Prednisone 50 mg at 13, 7, and 1 h before CT scan Diphenhydramine 25 mg 1 h before CT scan Prednisone 50 mg at 13, 7, and 1 h before CT scan Diphenhydramine 50 mg at 13, 7, and 1 h before CT scan
None
Prednisone 75 mg at 13, 7, and 1 h before CT scan Diphenhydramine 50 mg at 13, 7, and 1 h before CT scan
Prednisone 50 mg at 12, 18, 24, and 30 h after CT scan, and 25 mg at 36, 42, 48, and 54 h after CT scan Diphenhydramine 50 mg every 12 h after CT scan until prednisone completed Prednisone 75 mg at 12, 18, 24, and 30 h after CT scan, and 25 mg at 36, 42, 48, and 54 h after CT scan Diphenhydramine 50 mg every 12 h after CT scan until prednisone completed
CT, computed tomography; RRD, radiation recall dermatitis.
swelling. Despite higher premedication doses, she again developed RRD; however, the intensity was markedly decreased. She remained compliant with anastrozole and denied having taken new medications.
Discussion RRD is rare and characterized by sharply defined borders that correlate to prior radiation fields. Similarly, radiation recall involving deep tissues arises in prior treatment fields. 2,3 To reduce confounding factors, RRD has been defined as occurring (1) more than 7 days after radiotherapy and (2) after complete recovery of acute radiation toxicity. 1 Here, we present a case of RRD precipitated by nonionic contrast in a patient with preexisting sensitivity to iodine-based contrast. The unique circumstances of this case provide new insight into this poorly understood syndrome. Radiation recall is commonly associated with chemotherapeutic agents and recently has been described with targeted therapies, endocrine therapy, antibiotic drugs, and
Figure 1
statins (Table 2). This patient experienced RRD 3 times in the absence of new medications, each time associated with administration of nonionic contrast. Notably, anastrozole was recently associated with RRD. 4 This patient was compliant with daily anastrozole leading up to, during, and after each consecutive event. Therefore, RRD was likely related to the imaging study rather than anastrozole. CT scan radiation has not been linked to RRD, but there are 2 reports of RRD attributed to extensive sunlight exposure. 5,6 Moreover, there is 1 case of recall dermatitis after CT scan with contrast in the distribution of laser hair removal that occurred 3 days prior. 7 In the current case, each CT scan was performed with nonionic contrast, and it is difficult to discern whether RRD was precipitated by CT radiation itself or intravenous contrast; however, given an allergy to iodinated contrast, we favor this as the triggering agent. Taken together, RRD can be precipitated by a variety of agents, including nontherapeutic agents. RRD has been reported to recur at attenuated, similar, or worsened intensity with rechallenge, or it may not recur at all. 1,2 Moreover, RRD may subside spontaneously with
Acute radiation dermatitis. A, Pretreatment skin tone; B, dermatitis while on treatment; C, treatment plan skin rendering.
Practical Radiation Oncology: July-August 2015
Figure 2 Second episode of recall dermatitis 18 weeks after radiation.
continuation of the precipitating medications. 8 RRD is typically managed by withdrawal of the offending agent and pulse corticosteroids, although there is minimal evidence to support this practice. Although rechallenge resulted in serial attenuation in this case, it remains unclear whether this was secondary to escalated premedication. Nonetheless, we plan to continue the escalated anti-inflammatory regimen for this patient during future exposures to iodinated contrast. Another consideration for patients with radiation recall reactions limited to the skin is the use of topical corticosteroids or diphenhydramine, which has been described with promising results in recent cases. 9
Table 2
Medications associated with radiation recall
Cancer therapies Alkylating agents Anthracyclines Antimetabolite agents Antifolate agents Aromatase inhibitors Histone deacetylase inhibitors Kinase inhibitors Microtubule stabilizers Monoclonal antibodies mTOR inhibitors Nucleosides Platinum-based agents Selective estrogen receptor modulators Somatostatin analogs Topoisomerase inhibitors Vinca alkaloids Other Amphetamines Antibiotic agents Calcium channel blockers Herbal supplements NSAIDs Statins mTOR, mammalian target of rapamycin; NSAIDS, nonsteroidal anti-inflammatory agents.
Radiation recall
265
The pathogenesis of radiation recall is unknown, and there is no reliable method of identifying patients at risk. Several proposed mechanisms include activation of inflammatory pathways, vascular damage, and progenitor cell depletion or sensitization. 1 Hypothesis validation is difficult because of the rarity and unpredictability of radiation recall. Histologic analysis of RRD has demonstrated nonspecific inflammatory infiltrate. 7,10,11 In this patient with preexisting allergy to iodine-based contrast, RRD was likely precipitated by nonionic contrast. One explanation of this observation is that radiation predisposes local tissues to delayed-type hypersensitivity reactions through currently unidentified mechanisms, possibly by altering the cellular composition. Given their variable presentation, radiation recall syndromes may be composed of a heterogeneous group with similar presentations caused by distinct mechanisms. Reactions to iodinated radiocontrast can be acute or delayed and are thought to be caused by idiosyncratic or T-cell–mediated hypersensitivity reactions, respectively. 12 Risk factors for adverse reactions include history of prior reactions to radiocontrast, asthma, and atopy, all of which this patient had. 12 Monomeric nonionic contrast (as used at our institution) has the lowest risk of adverse reaction, whereas dimeric nonionic contrast has the highest risk. 13 Although prophylactic corticosteroids are commonly used once sensitivity is identified, breakthrough reactions can still occur. Thus, many similarities exist between RRD and hypersensitivity to iodinated contrast, and it is likely they share a common mechanism. In this patient, radiation exposure localized a previously generalized reaction, which suggests radiation-induced sensitization of the local tissue that predisposed it to future events. To the best of our knowledge, this is the first report both of RRD caused by iodinated contrast and of RRD precipitated by a prior allergen despite high-dose premedication. These unique circumstances are suggestive of a radiation-related, delayed-type hypersensitivity reaction. However, the underlying molecular mechanisms of RRD and its optimal management remain unknown.
References 1. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol. 2001;59:237-245. 2. Azria D, Magné N, Zouhair A, et al. Radiation recall: A well recognized but neglected phenomenon. Cancer Treat Rev. 2005;31:555-570. 3. Jeter MD, Jänne PA, Brooks S, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53:394-400. 4. Haydaroglu A, Sert F, Kazandi AC, Unal I. Radiation recall reaction with anastrozole treatment in breast cancer. Pract Radiat Oncol. 2012;2:e65-e68. 5. Del Guidice SM, Gerstley JK. Sunlight-induced radiation recall. Int J Dermatol. 1988;27:415-416. 6. Le Scodan R, Wyplosz B, Couchon S, Housset M, Laccourreye O. UV-light induced radiation recall dermatitis after a chemoradiotherapy organ preservation protocol. Eur Arch Otorhinolaryngol. 2007;264: 1099-1102.
266
S.K.M. Lau, A. Rahimi
7. Córdoba S, Tardío JC, Utrera M, Martínez-Morán C, Borbujo J. Laser recall dermatitis. JAMA Dermatol. 2014;150:212-213. 8. Extermann M, Vogt N, Forni M, Dayer P. Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol. 1995;48:77-78. 9. Boussemart L, Boivin C, Claveau J, et al. Vemurafenib and radiosensitization. JAMA Dermatol. 2013;149:855-857. 10. Boström A, Sjölin-Forsberg G, Wilking N, Bergh J. Radiation recall: Another call with tamoxifen. Acta Oncol. 1999;38:955-959.
Practical Radiation Oncology: July-August 2015 11. Castellano D, Hitt R, Cortés-Funes H, Romero A, Rodriguez-Peralto JL. Side effects of chemotherapy: Case 2: Radiation recall reaction induced by gemcitabine. J Clin Oncol. 2000;18:695-696. 12. Pasternak JJ, Williamson EE. Clinical pharmacology, uses, and adverse reactions of iodinated contrast agents: A primer for the non-radiologist. Mayo Clin Proc. 2012;87:390-402. 13. Sutton AG, Finn P, Grech ED, et al. Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization. Am Heart J. 2001;141:677-683.
